Benzothiazepine and benzothiazepine derivatives with ileal bile acid transport (IBAT) inhibotory activity for the treatment hyperlipidaemia

ABSTRACT

The present invention relates to compounds of formula (I) wherein R v , R 1 , R 2 , R x , R y , M, R z , v, R 3 , R 4 , R 5  and R 6  are as defined within; pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as ileal bile acid transport (IBAT) inhibitors for the treatment of hyperlipidaemia. Processes for their manufacture and pharmaceutical compositions containing them are also described.

This application is a 371 of PCT/GB02/04033, filed Sep. 5, 2002.

This invention relates to benzothiazepine and benzothiadiazepinederivatives, or pharmaceutically acceptable salts, solvates, solvates ofsuch salts and prodrugs thereof. These benzothiazepines andbenzothiadiazepines possess ileal bile acid transport (IBAT) inhibitoryactivity and accordingly have value in the treatment of disease statesassociated with hyperlipidaemic conditions and they are useful inmethods of treatment of a warm-blooded animal, such as man. Theinvention also relates to processes for the manufacture of saidbenzothiazepine and benzothiadiazepine derivatives, to pharmaceuticalcompositions containing them and to their use in the manufacture ofmedicaments to inhibit IBAT in a warm-blooded animal, such as man.

It is well-known that hyperlipidaemic conditions associated withelevated concentrations of total cholesterol and low-density lipoproteincholesterol are major risk factors for cardiovascular atheroscleroticdisease (for instance “Coronary Heart Disease: Reducing the Risk; aWorldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999,100, 1930–1938 and “Diabetes and Cardiovascular Disease: A Statement forHealthcare Professionals from the American Heart Association” Grundy S,Benjamin I., Burke G., et al; Circulation, 1999, 100, 1134–46).Interfering with the circulation of bile acids within the lumen of theintestinal tracts is found to reduce the level of cholesterol. Previousestablished therapies to reduce the concentration of cholesterolinvolve, for instance, treatment with HMG-CoA reductase inhibitors,preferably statins such as simvastatin and fluvastatin, or treatmentwith bile acid binders, such as resins. Frequently used bile acidbinders are for instance cholestyramine and cholestipol. One recentlyproposed therapy (“Bile Acids and Lipoprotein Metabolism: a Renaissancefor Bile Acids in the Post Statin Era” Angelin B, Eriksson M, Rudling M;Current Opinion on Lipidology, 1999, 10, 269–74) involved the treatmentwith substances with an IBAT inhibitory effect.

Re-absorption of bile acid from the gastrointestinal tract is a normalphysiological process which mainly takes place in the ileum by the IBATmechanism. Inhibitors of IBAT can be used in the treatment ofhypercholesterolaemia (see for instance “Interaction of bile acids andcholesterol with nonsystemic agents having hypocholesterolaemicproperties”, Biochemica et Biophysica Acta, 1210 (1994) 255–287). Thus,suitable compounds having such inhibitory IBAT activity are also usefullin the treatment of hyperlipidaemic conditions. Substituted compoundspossessing such IBAT inhibitory activity have been described, see forinstance hypolipidaemic compounds described in WO 93/16055, WO 94/18183,WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO00/38729, WO 01/68906 and EP 0 864 582.

A further aspect of this invention relates to the use of the compoundsof the invention in the treatment of dyslipidemic conditions anddisorders such as hyperlipidaemia, hypertrigliceridemia,hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (highVLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia,hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). Inaddition, these compounds are expected to be useful for the preventionand treatment of different clinical conditions such as atherosclerosis,arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vasculardysfunction, endothelial dysfunction, heart failure, coronary heartdiseases, cardiovascular diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, inflammation of cardiovasculartissues such as heart, valves, vasculature, arteries and veins,aneurisms, stenosis, restenosis, vascular plaques, vascular fattystreaks, leukocytes, monocytes and/or macrophage infiltration, intimalthickening, medial thinning, infectious and surgical trauma and vascularthrombosis, stroke and transient ischaemic attacks.

The present invention is based on the discovery that certainbenzothiazepine and benzothiadiazepine compounds surprisingly inhibitIBAT. Such properties are expected to be of value in the treatment ofdisease states associated with hyperlipidaemic conditions.

Accordingly, the present invention provides a compound of formula (I):

wherein:

R^(v) is selected from hydrogen or C₁₋₆alkyl;

One of R¹ and R² are selected from hydrogen, C₁₋₆alkyl or C₂₋₆alkenyland the other is selected from C₁₋₆alkyl or C₂₋₆alkenyl;

R^(x) and R^(y) are independently selected from hydrogen, hydroxy,amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

M is selected from —N— or —CH—;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0–5;

one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino,N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0–2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (IB) or (IC):

wherein:

Y is —N(R^(n))—, —N(R^(n))C(O)—,—N(R^(n))C(O)(CR^(s)R^(t))_(v)N(R^(n))C(O)—,—O—, and —S(O)_(a)—; whereina is 0–2, v is 1–2, R^(s) and R^(t) are independently selected fromhydrogen or C₁₋₄alkyl optionally substituted by R²⁶ and R^(n) ishydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₆alkyl,carbocyclyl or heterocyclyl; and when q is 0, R¹⁴ may additionally beselected from hydroxy; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1–3; wherein the values of R¹³ may be the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–3; wherein the values of R⁷ may be the same or different;

Ring B is a nitrogen linked heterocyclyl substituted on carbon by onegroup selected from R²³, and optionally additionally substituted oncarbon by one or more R²⁴; and wherein if said nitrogen linkedheterocyclyl contains an —NH— moiety, that nitrogen may be optionallysubstituted by a group selected from R²⁵;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alklanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amnio, C₁₋₄alkanoylamino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may beindependently optionally substituted on carbon by one or more R²¹;

R¹⁹, R²⁰, R²⁴ and R²⁶ are independently selected from halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄aylkyl)₂amino,C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl,C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl,N-(C₁₋₄alkyl)sulphamoyl, N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl,heterocyclyl, benzyloxycarbonylamino, (C₁₋₄alkyl)₃silyl, sulpho,sulphino, amidino, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)),—P(O)(OH)(R^(a)) or —P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) areindependently selected from C₁₋₆alkyl; wherein R¹⁹, R²⁰, R²⁴ and R²⁶ maybe independently optionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

R²³ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(g))(OR^(h)),—P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or —P(O)(OR^(g))(R^(h)) whereinR^(g) and R^(h) are independently selected from C₁₋₆alkyl;

R²⁵ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

According to a further aspect of the present invention there is provideda compound of formula (I):

wherein:

R^(v) is selected from hydrogen or C₁₋₆alkyl;

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the otheris selected from C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen, hydroxy,amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

M is selected from —N— or —CH—;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0–5;

one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino,N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0–2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (IB):

wherein:

Y is —N(R^(n))—, —N(R^(n))C(O)—, —O—, and —S(O)_(a); wherein a is 0–2and R^(n) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1–3; wherein the values of R¹³ maybe the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–3; wherein the values of R⁷ may be the same or different;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a),wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄akyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may be independentlyoptionally substituted on carbon by one or more R²¹;

R¹⁹ and R²⁰ are independently selected from halo, nitro, cyano, hydroxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl,N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino,amidino, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)),—P(O)(OH)(R^(a)) or —P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) areindependently selected from C₁₋₆alkyl; wherein R¹⁹ and R²⁰ may beindependently optionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

According to a further aspect of the present invention there is provideda compound of formula (I):

wherein:

R^(v) is selected from hydrogen or C₁₋₆alkyl;

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the otheris selected from C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen, hydroxy,amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

M is selected from —N— or —CH—;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl;

v is 0–5;

one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino,N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0–2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (IB) or (IC):

wherein:

Y is —N(R^(n))—, —N(R^(n))C(O)—,—N(R^(n))C(O)(CR^(s)R^(t))_(v)N(R^(n))C(O)—, —O—, and —S(O)a—; wherein ais 0–2, v is 1–2, R^(s) and R^(t) are independently selected fromhydrogen or C₁₋₄alkyl optionally substituted by R²⁶ and R^(n) ishydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; and when q is 0, R¹⁴ may additionally beselected from hydroxy; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1–3; wherein the values of R¹³ may be the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–3; wherein the values of R⁷ may be the same or different;

Ring B is a nitrogen linked heterocyclyl substituted on carbon by onegroup selected from R²³, and optionally additionally substituted oncarbon by one or more R²⁴; and wherein if said nitrogen linkedheterocyclyl contains an —NH— moiety, that nitrogen may be optionallysubstituted by a group selected from R²⁵;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may beindependently optionally substituted on carbon by one or more R²¹;

R¹⁹, R²⁰, R²⁴ and R²⁶ are independently selected from halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino,C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl,C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl,N-(C₁₋₄alkyl)sulphamoyl, N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl,heterocyclyl, benzyloxycarbonylamino, sulpho, sulphino, amidino,phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)), —P(O)(OH)(R^(a)) or—P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) are independently selectedfrom C₁₋₆alkyl; wherein R¹⁹, R²⁰, R²⁴ and R²⁶ may be independentlyoptionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

R²³ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(g))(OR^(h)),—P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or —P(O)(OR^(g))(R^(h)) whereinR^(g) and R^(h) are independently selected from C₁₋₆alkyl;

R²⁵ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” includes C₁₋₄alkyl, C₁₋₃alkyl, propyl, isopropyland t-butyl. However, references to individual alkyl groups such as‘propyl’ are specific for the straight chained version only andreferences to individual branched chain alkyl groups such as ‘isopropyl’are specific for the branched chain version only. A similar conventionapplies to other radicals, for example “phenylC₁₋₆alkyl” would includephenylC₁₋₆alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term“halo” refers to fluoro, chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

“Heteroaryl” is a totally unsaturated, mono or bicyclic ring containing3–12 atoms of which at least one atom is chosen from nitrogen, sulphuror oxygen, which may, unless otherwise specified, be carbon or nitrogenlinked. Preferably “heteroaryl” refers to a totally unsaturated,monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms of which at least one atom is chosen from nitrogen, sulphuror oxygen, which may, unless otherwise specified, be carbon or nitrogenlinked. Examples and suitable values of the term “heteroaryl” arethienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl,triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyland quinolyl. Preferably the term “heteroaryl” refers to thienyl orindolyl.

“Aryl” is a totally unsaturated, mono or bicyclic carbon ring thatcontains 3–12 atoms. Preferably “aryl” is a monocyclic ring containing 5or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable valuesfor “aryl” include phenyl or naphthyl. Particularly “aryl” is phenyl.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 3–12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a —CH₂— group canoptionally be replaced by a —C(O)— or a ring sulphur atom may beoptionally oxidised to form the S-oxides. Preferably a “heterocyclyl” isa saturated, partially saturated or unsaturated, mono or bicyclic ringcontaining 5 or 6 atoms of which at least one atom is chosen fromnitrogen, sulphur or oxygen, which may, unless otherwise specified, becarbon or nitrogen linked, wherein a —CH₂— group can optionally bereplaced by a —C(O)— or a ring sulphur atom may be optionally oxidisedto form S-oxide(s). Examples and suitable values of the term“heterocyclyl” are thiazolidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl,1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl,2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl,1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl,4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl,2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl,1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino,1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl,homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl,thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl pyranyl,indolyl, pyrrimdyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl,4-pyridonyl, quinolyl and 1-isoquinolonyl.

A “nitrogen linked heterocyclyl” is a saturated, partially saturated orunsaturated, mono or bicyclic ring containing 3–12 atoms of which atleast one atom is nitrogen and the heterocyclyl is linked to thecarbonyl group of formula (IC) via this nitrogen, which may additionallycontain further heteroatoms chosen from nitrogen, sulphur or oxygen,wherein a —CH₂— group can optionally be replaced by a —C(O)— or a ringsulphur atom may be optionally oxidised to form the S-oxides. Preferablya “nitrogen linked heterocyclyl” is a saturated, partially saturated orunsaturated, mono or bicyclic ring containing 5 or 6 atoms of which atleast one atom is nitrogen and the heterocyclyl is linked to thecarbonyl group of formula (IC) via this nitrogen, which may additionallycontain further heteroatoms chosen from nitrogen, sulphur or oxygen,wherein a —CH₂— group can optionally be replaced by a —C(O)— or a ringsulphur atom may be optionally oxidised to form the S-oxides. Examplesand suitable values of the term “nitrogen linked heterocyclyl” aremorpholino, pyrrolidin-1-yl, imidazol-1-yl, pyrazolidin-1-yl,piperidin-1-yl and piperazin-1-yl. Particularly a “nitrogen linkedheterocyclyl” is pyrrolidin-1-yl.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic carbon ring that contains 3–12 atoms; wherein a —CH₂— groupcan optionally be replaced by a —C(O)—. Preferably “carbocyclyl” is amonocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl,cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.Particularly “carbocyclyl” is cyclopropyl, cyclobutyl, 1-oxocyclopentyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or1-oxoindanyl.

An example of “C₁₋₆alkanoyloxy” and “C₁₋₄alkanoyloxy” is acetoxy.Examples of “C₁₋₆alkoxycarbonyl” and “C₁₋₄alkoxycarbonyl” includemethoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of“C₁₋₆alkoxy” and “C₁₋₄alkoxy” include methoxy, ethoxy and propoxy.Examples of “C₁₋₆alkanoylamino” and “C₁₋₄alkanoylamino” includeformamido, acetamido and propionylamino. Examples of “C₁₋₆alkylS(O)_(a)wherein a is 0 to 2” and “C₁₋₄alkylS(O)_(a) wherein a is 0 to 2” includemethylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl andethylsulphonyl. Examples of “C₁₋₆alkanoyl” and “C₁₋₄alkanoyl” includepropionyl and acetyl. Examples of “N-(C₁₋₆alkyl)amino” and“N-(C₁₋₄alkyl)amino” include methylamino and ethylamino. Examples of“N,N-(C₁₋₆alkyl)₂amino” and “N,N-(C₁₋₄alkyl)₂amino” includedi-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examplesof “C₂₋₆alkenyl” and “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl.Examples of “C₂₋₆alkynyl” and “C₂₋₄alkynyl” are ethynyl, 1-propynyl and2-propynyl. Examples of “N-(C₁₋₆alkyl)sulphamoyl” and“N-(C₁₋₄alkyl)sulphamoyl” are N-(C₁₋₃alkyl)sulphamoyl,N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of“N-(C₁₋₆alkyl)₂sulphamoyl” “N-(C₁₋₄alkyl)₂sulphamoyl” areN,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of“N-(C₁₋₆alkyl)carbamoyl” and “N-(C₁₋₄alkyl)carbamoyl” aremethylaminocarbonyl and ethylaminocarbonyl. Examples of“N,N-(C₁₋₆alkyl)₂carbamoyl” and “N,N-(C₁₋₄alkyl)₂carbamoyl” aredimethylaminocarbonyl and methylethylaminocarbonyl. Example of“C₁₋₆alkylsulphonyl” are mesyl and ethylsulphonyl. Examples of“(C₁₋₄alkyl)₃silyl,” include trimethylsilyl and methyldiethylsilyl.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric, acetic or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

The compounds of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). examples of pro-drugs include in vivohydrolysable esters and in vivo hydrolysable amides of a compound of theformula (I).

An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol. Suitable pharmaceutically acceptableesters for carboxy include C₁₋₆alkoxymethyl esters for examplemethoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

A suitable value for an in vivo hydrolysable amide of a compound of theformula (I) containing a carboxy group is, for example, a N-C₁₋₆alkyl orN,N-di-C₁₋₆alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess IBAT inhibitoryactivity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess IBAT inhibitory activity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess IBAT inhibitory activity.

Particular values are as follows. Such values maybe used whereappropriate with any of the definitions, claims or embodiments definedhereinbefore or hereinafter.

R^(v) is hydrogen.

R¹ and R² are C₁₋₄alkyl.

R¹ and R² are both butyl.

One of R¹ and R² is ethyl and the other is butyl.

One of R^(x) and R^(y) is hydrogen and the other is hydroxy.

R^(x) and R^(y) are both hydrogen.

M is —N—.

M is —CH—.

v is 0 or 1.

v is 0.

R^(z) is C₁₋₄alkyl.

R³ and R⁶ are hydrogen.

R⁴ is methylthio or bromo.

R⁴ is methylthio.

R⁴ is halo, C₁₋₄alkyl or C₁₋₄alkylS(O)_(a) wherein a is 0.

R⁴ is bromo, methyl or methylthio.

R⁵ is a group of formula (IA) (as depicted above) wherein:

X is —O—;

Ring A is phenyl optionally substituted by one or more substituentsselected from R¹⁷;

n is 1;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

m is 0;

R¹¹ is a group of formula (IB) (as depicted above) wherein:

R¹² is hydrogen;

p is 1 or 2;

R¹³ is hydrogen;

q is 0;

r is 0;

R¹⁵ is carboxy or sulpho; and

R¹⁷ is hydroxy.

R⁵ is N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy, orN-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy.

R⁵ is a group of formula (IA) (as depicted above) wherein:

X is —O—;

Ring A is phenyl optionally substituted by one or more substituentsselected from R¹⁷;

n is 1;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

m is 0;

R¹¹ is carboxy, a group of formula (IB) (as depicted above) or a groupof formula (IC) (as depicted above) wherein:

R¹² is hydrogen or C₁₋₄alkyl;

p is 1 or 2;

R¹³ is hydrogen or C₁₋₄alkyl optionally substituted by R²⁰ wherein R²⁰is hydroxy, carbamoyl, amino, benzyloxycarbonylamino orC₁₋₄alkylS(O)_(a) wherein a is 0;

R¹⁴ is hydrogen or hydroxy;

q is 0;

r is 0 or 1;

R¹⁵ is carboxy or sulpho;

R¹⁷ is hydroxy; and

Ring B is pyrrolidin-1-yl substituted on carbon by one group selectedfrom R²³; wherein R²³ is carboxy.

R⁵ is N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-carbamoylethyl)-carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-3-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(1-(S)-1-carboxy-2-(S)-2-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-4-aminobutyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-{N-[(S)-1-carboxy-4-(benzyloxycarbonylamino)butyl]carbamoyl}benzyl)carbamoylmethoxy,N-[(R)-α-((S)-2-carboxypyrrolidin-1-ylcarbonyl)benzyl]carbamoylmethoxy,N-{(R)-α-[N-(carboxymethyl)-N-methylcarbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(1-(R)-2-(R)-1-carboxy-1-hydroxyprop-2-yl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(sulphomethyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-carboxybenzyl)carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxyorN-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy.

R⁵ is a group of formula (IA) (as depicted above) wherein:

X is —O—;

Ring A is phenyl optionally substituted by one or more substituentsselected from R¹⁷;

n is 1;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

m is 0;

R¹¹ is carboxy, a group of formula (IB) (as depicted above) or a groupof formula (IC) (as depicted above) wherein:

R¹² is hydrogen or C₁₋₄alkyl;

p is 1 or 2;

R¹³ is hydrogen or C₁₋₆alkyl optionally substituted by R²⁰ wherein R²⁰is hydroxy, carbamoyl, amino, benzyloxycarbonylamino, C₁₋₄alkylS(O)_(a)wherein a is 0 or (C₁₋₄alkyl)₃silyl;

R¹⁴ is hydrogen or hydroxy or C₁₋₆alkyl; wherein R¹⁴ may be optionallysubstituted by one or more substituents selected from R²⁰;

Y is —N(R^(n))C(O)— wherein R^(n) is hydrogen;

q is 0 or 1;

r is 0 or 1;

R¹⁵ is carboxy or sulpho;

R¹⁷ is hydroxy; and

R²⁰ is selected from hydroxy;

Ring B is pyrrolidin-1-yl or azetidinyl substituted on carbon by onegroup selected from R²³, and optionally additionally substituted oncarbon by one or more R²⁴; wherein R²³ is carboxy and R²⁴ is hydroxy.

R⁵ is N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-carbamoyl-ethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-({(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-3-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(1-(S)-1-carboxy-2-(S)-2-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-4-aminobutyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-{N-[(S)-1-carboxy-4-(benzyloxycarbonylamino)butyl]carbamoyl}benzyl)carbamoylmethoxy,N-[(R)-α-((S)-2-carboxypyrrolidin-1-ylcarbonyl)benzyl]carbamoylmethoxy,N-{()-α-[N-(carboxymethyl)-N-methylcarbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(1-(R)-2-(R)-1-carboxy-1-hydroxyprop-2-yl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(sulphomethyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-carboxybenzyl)carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-2methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[2-(S)-2-(carboxy)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl}carbamoylmethoxy,N-{(R)-α-[2-(S)-2-(carboxy)azetidin-1-ylcarbonyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-{(S)-1-[N-((S)-1-carboxyethyl)carbamoyl]ethyl}carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(R)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-3,3-dimethylbutyl)carbamoyl}-4-hydroxybenzyl}carbamoylmethoxy,N-((R)-α-{(N-[(S)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxyorN-((R)-α-{N-[(R)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4hydroxybenzyl)carbamoylmethoxy.

R⁵ is hydrogen.

R⁴ is a group of formula (IA).

R⁵ is a group of formula (IA).

Therefore in an further aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

R^(v) is hydrogen;

R¹ and R² are C₁₋₄alkyl;

R^(x) and R^(y) are both hydrogen;

M is —N—;

v is 0;

R³ and R⁶ are hydrogen;

R⁴ is halo, C₁₋₄alkyl or C₁₋₄alkylS(O)_(a) wherein a is 0;

R⁵ is a group of formula (IA) (as depicted above) wherein:

X is —O—;

Ring A is phenyl optionally substituted by one or more substituentsselected from R¹⁷;

n is 1;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

m is 0;

R¹¹ is carboxy, a group of formula (IB) (as depicted above) or a groupof formula (IC) (as depicted above) wherein:

R¹² is hydrogen or C₁₋₄alkyl;

p is 1 or 2;

R¹³ is hydrogen or C₁₋₆alkyl optionally substituted by R²⁰ wherein R²⁰is hydroxy, carbamoyl, amino, benzyloxycarbonylamino, C₁₋₄alkylS(O)_(a)wherein a is 0 or (C₁₋₄alkyl)₃silyl;

R¹⁴ is hydrogen or hydroxy or C₁₋₆alkyl; wherein R¹⁴ may be optionallysubstituted by one or more substituents selected from R²⁰;

Y is —N(R^(n))C(O)— wherein R^(n) is hydrogen;

q is 0 or 1;

r is 0 or 1;

R¹⁵ is carboxy or sulpho;

R¹⁷ is hydroxy; and

R²⁰ is selected from hydroxy; and

Ring B is pyrrolidin-1-yl or azetidinyl substituted on carbon by onegroup selected from R²³, and optionally additionally substituted oncarbon by one or more R²⁴; wherein R²³ is carboxy and R²⁴ is hydroxy; ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

R^(v) is hydrogen;

R¹ and R² are both butyl;

R^(x) and R^(y) are both hydrogen;

M is —N—;

v is 0;

R³ and R⁶ are hydrogen;

R⁴ is bromo, methyl or methylthio; and

R⁵ is N-{(R)-α-[N-(carboxymethyl)carbamoyl]benyzl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(R)-1-carboxy-2-methylthio-ethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-carbamoyl-ethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl)]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-3-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(1-(S)-1-carboxy-2-(S)-2-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-4-aminobutyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-{N-[(S)-1-carboxy-4-(benzyloxycarbonylamino)butyl]carbamoyl}benzyl)carbamoylmethoxy,N-[(R)-α-((S)-2-carboxypyrrolidin-1-ylcarbonyl)benzyl]carbamoylmethoxy,N-{(R)-α-[N-(carboxymethyl)-N-methylcarbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(1-(R)-2-(R)-1-carboxy-1-hydroxyprop-2-yl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(sulphomethyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-carboxybenzyl)carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[2-(S)-2-(carboxy)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl}carbamoylmethoxy,N-{(R)-α-[2-(S)-2-(carboxy)azetidin-1-ylcarbonyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-{(S)-1-[N-((S)-1-carboxyethyl)carbamoyl]ethyl}carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(R)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-3,3-dimethylbutyl)carbamoyl]-4hydroxybenzyl}carbamoylmethoxy,N-((R)-α-{N-[(S)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4-hydroxybenzy)carbamoylmethoxyorN-((R)-α-{N-[(R)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of examples 5, 6, 7, 9, 11, 14, 15, 26, 27, 28, 30 or 33 ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of the examples or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

Preferred aspects of the invention are those which relate to thecompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (I) or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof which process(wherein variable groups are, unless otherwise specified, as defined informula (I) comprises of:

-   Process 1): for compounds of formula (I) wherein X is —O—,—NR^(a) or    —S—; reacting a compound of formula (IIa) or (IIb):

-    with a compound of formula (III):

-    wherein L is a displaceable group;-   Process 2): reacting an acid of formula (IVa) or (IVb):

-    or an activated derivative thereof; with an amine of formula (V):

-   Process 3): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB); reacting a compound of formula (I) wherein R¹¹ is    carboxy with an amine of formula (VI):

-   Process 4) for compounds of formula (I) wherein one of R⁴ and R⁵ are    independently selected from C₁₋₆alkylthio optionally substituted on    carbon by one or more R¹⁷; reacting a compound of formula (VIIa) or    (VIIb):

-    wherein L is a displaceable group; with a thiol of formula (VIII):    R^(m)—H  (VIII)-    wherein R^(m) is C₁₋₆alkylthio optionally substituted on carbon by    one or more R¹⁶;-   Process 5): for compounds of formula (I) wherein R¹¹ is carboxy;    deprotecting a compound of formula (IXa):

-    wherein R^(p) together with the —OC(O)— group to which it is    attached forms an ester;-   Process 6): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB) and R¹⁵ is carboxy; deprotecting a compound of formula    (Xa):

-    wherein R^(p) together with the —OC(O)— group to which it is    attached forms an ester;-   Process 7): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB) and N(R^(n))C(O)—; reacting an acid of formula (XIa):

-    or an activated derivative thereof; with an amine of formula (XII):

-    and thereafter if necessary or desirable:-   i) converting a compound of the formula (I) into another compound of    the formula (I);-   ii) removing any protecting groups;-   iii) forming a pharmaceutically acceptable salt, solvate, solvate of    such a salt or a prodrug.

L is a displaceable group, suitable values for L are for example, ahalogeno or sulphonyloxy group, for example a chloro, bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group.

R^(p) together with the —OC(O)— group to which it is attached forms anester. Preferably R^(p) is methyl or ethyl. More preferably R^(p) ismethyl. In another aspect of the invention Rp is C₁₋₆alkyl orphenylC₁₋₆alkyl, preferably C₁₋₄alkyl or benzyl, more preferablyt-butyl, methyl, ethyl or benzyl.

Specific reaction conditions for the above reactions are as follows.

The bicyclic ring systems of the present invention may be assembledaccording to Scheme Ia or Scheme Ib. The skilled person will appreciateto make any of the above identified intermediates the value of R⁴ or R⁵in the following schemes would be replaced with the appropriate group.For example, to synthesize a compound of formula (IIa) R⁴ would be HX inthe following scheme.

Wherein FGI is functional interconversion of the Br into other values ofR⁴ using procedures known to the skilled person.

Compounds of formula (A) and (D) are commercially available, or they areknown in the literature, or they may be prepared by standard processesknown in the art.

-   Process 1): Compounds of formula (IIa) or (IIb) may be reacted with    compounds of formula (III) in the presence of a base for example an    inorganic base such as sodium carbonate, or an organic base such as    Hunigs base, in the presence of a suitable solvent such as    acetonitrile, dichloromethane or tetrahydrofuran at a temperature in    the range of 0° C. to reflux, preferably at or near reflux.

Compounds of formula (III) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

-   Process 2) and Process 3) and Process 7): Acids and amines may be    coupled together in the presence of a suitable coupling reagent.    Standard peptide coupling reagents known in the art can be employed    as suitable coupling reagents, or for example carbonyldiimidazole    and dicyclohexyl-carbodiimide, optionally in the presence of a    catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine,    optionally in the presence of a base for example triethylamine,    pyridine, or 2,6-di-alkyl-pyridines such as 2,6-lutidine or    2,6-di-tert-butylpyridine. Suitable solvents include    dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and    dimethylformamide. The coupling reaction may conveniently be    performed at a temperature in the range of −40 to 40° C.

Suitable activated acid derivatives include acid halides, for exampleacid chlorides, and active esters, for example pentafluorophenyl esters.The reaction of these types of compounds with amines is well known inthe art, for example they may be reacted in the presence of a base, suchas those described above, and in a suitable solvent, such as thosedescribed above. The reaction may conveniently be performed at atemperature in the range of −40 to 40° C.

Compounds of formula (IVa) or (IVb) wherein X=—O—,—NR^(a),—S— may beprepared according to Scheme 2:

Wherein L in (VIIa) and (VIIb) is a displaceable group e.g. bromo,chloro, fluoro, mesyl or tosyl and wherein X is —O—,—S—, NR^(a)(optionally for —SO— and —SO₂— followed by the oxidation step of Process1).

Compounds of formula (IVa) and (IVb) where X is —SO— or —SO₂— may beprepared by oxidising the resulting compounds of formula (IVa) and (IVb)from Scheme 2 where X is —S—.

Compounds of formula (Va) or (Vb) wherein X is —CH₂— and n is 1 may beprepared according to Scheme 3.

The skilled person will appreciate that the above reaction scheme may bemanipulated to prepare compounds of formula (Va) or (Vb) where n is 2 or3.

Compounds of formula (XIa) and (XIb) may be prepared by manipulationsknown to the skilled person of the processes described herein.

Compounds of formula (IVc), (V), (VI), (XII) and (VII) are commerciallyavailable compounds, or they are known in the literature, or they areprepared by standard processes known in the art.

-   Process 4): Compounds of formula (VIIa) and (VIIb) maybe reacted    with thiols of formula (VIII) in the presence of base, for example    an inorganic base such as sodium carbonate or an organic base such    as Hunigs base, in the presence of a suitable solvent such as DMF or    THF at a temperature in the range of 0° C. to reflux.

Compounds of formula (VIIa) and (VIIb) may be prepared by any of theprocedures above for the preparation of compounds of formula (I), butwherein one of R⁴ and R⁵ is L.

Compounds of formula (VII) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

-   Process 5) and Process 6): Esters of formula (IXa), (IXb), (Xa) and    (Xb) may be deprotected under standard conditions such as those    described below, for Example they may be deprotected with sodium    hydroxide in methanol at room temperature.

Esters of formula (IXa), (IXb), (Xa) and (Xb) may be prepared by any ofthe procedures above for the preparation of compounds of formula (I),but wherein R¹¹ or R¹⁵ is C₁₋₄alkoxycarbonyl.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. A particular instance where a protecting group may be used is inprotecting the nitrogen in the 2-position of the benzothiadiazepine ringduring the synthesis of certain intermediates.

Conventional protecting groups may be used in accordance with standardpractice (for illustration see T. W. Green, Protective Groups in OrganicSynthesis, John Wiley and Sons, 1999). Thus, if reactants include groupssuch as amino, carboxy or hydroxy it maybe desirable to protect thegroup in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which mayberemoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoy, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifing group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present inventionpossess IBAT inhibitory activity. These properties may be assessed, forexample, using an in vitro test assay for studying the effect on bileacid uptake in IBAT-transfected cells (Smith L., Price-Jones M. J.,Hugnes K. T. and Jones N. R. A.; J Biomolecular Screening, 3, 227–230)or in vivo by studying the effect on radiolabelled bile acid absorptionin mice/rats (Lewis M. C., Brieaddy L. E. and Root C., J., J Lip Res1995, 36, 1098–1105).

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, will normally beadministered to a warm-blooded animal at a unit dose within the range5–5000 mg per square meter body area of the animal, i.e. approximately0.02–100 mg/kg, preferably 0.02–50 mg/kg, and this normally provides atherapeutically-effective dose. A unit dose form such as a tablet orcapsule will usually contain, for example 1–250 mg of active ingredient.Preferably a daily dose in the range of 1–50 mg/kg, particularly 0.1–10mg/kg is employed. In another aspect a daily dose in the rage of 0.02–20mg/kg is employed. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

According to a further aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use in a method of prophylactic or therapeutictreatment of a warm-blooded animal, such as man.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, are effective IBAT inhibitors, and accordingly havevalue in the treatment of disease states associated with hyperlipidaemicconditions.

Thus according to this aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use as a medicament.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in theproduction of an IBAT inhibitory effect in a warm-blooded animal, suchas man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in the treatmentof hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in the treatmentof dyslipidemic conditions and disorders such as hyperlipidaemia,hypertrigliceridemia, hyperbetalipoproteinemia (high LDL),hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia,hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia andhypoalphalipoproteinemia (low HDL) in a warm-blooded animal, such asman.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in the treatmentof different clinical conditions such as atherosclerosis,arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vasculardysfunction, endothelial dysfunction, heart failure, coronary heartdiseases, cardiovascular diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, inflammation of cardiovasculartissues such as heart, valves, vasculature, arteries and veins,aneurisms, stenosis, restenosis, vascular plaques, vascular fattystreaks, leukocytes, monocytes and/or macrophage infiltration, intimalthickening, medial thinning, infectious and surgical trauma and vascularthrombosis, stroke and transient ischaemic attacks in a warm-bloodedanimal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in the treatmentof atherosclerosis, coronary heart diseases, myocardial infarction,angina pectoris, peripheral vascular diseases, stroke and transientischaemic attacks in a warm-blooded animal, such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating dyslipidemic conditions and disorders suchas hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (highLDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia,hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia andhypoalphalipoproteinemia (low HDL) in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating different clinical conditions such asatherosclerosis, arteriosclerosis, arrhythmia, hyper-thromboticconditions, vascular dysfunction, endothelial dysfunction, heartfailure, coronary heart diseases, cardiovascular diseases, myocardialinfarction, angina pectoris, peripheral vascular diseases, inflammationof cardiovascular tissues such as heart, valves, vasculature, arteriesand veins, aneurisms, stenosis, restenosis, vascular plaques, vascularfatty streaks, leukocytes, monocytes and/or macrophage infiltration,intimal thickening, medial thinning, infectious and surgical trauma andvascular thrombosis, stroke and transient ischaemic attacks in need ofsuch treatment which comprises administering to said animal an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating atherosclerosis, coronary heart diseases,myocardial infarction, angina pectoris, peripheral vascular diseases,stroke and transient ischaemic attacks in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

There is evidence that an IBAT inhibitor might potentially be useful inthe treatment and/or prevention of gallstones. According to a furtherfeature of this aspect of the invention there is provided a method oftreating and/or preventing gallstones in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

The size of the dose required for the therapeutic or prophylactictreatment will necessarily be varied depending on the host treated, theroute of administration and the severity of the illness being treated. Aunit dose in the range, for example, 0.1–50 mg/kg preferably 0.1–10mg/kg is envisaged.

The IBAT inhibitory activity defined hereinbefore may be applied as asole therapy or may involve, in addition to a compound of the invention,one or more other substances and/or treatments. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. Accordingto this aspect of the invention there is provided a pharmaceuticalproduct comprising a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,as defined hereinbefore and an additional IBAT inhibitory substance asdefined hereinbefore and an additional hypolipidaemic agent for theconjoint treatment of hyperlipidaemia.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with an HMG Co-Areductase inhibitor, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable HMG Co-A reductaseinhibitors, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are statins well known in the art.Particular statins are fluvastatin, lovastatin, pravastatin,simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin,mevastatin and(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof. Aparticular statin is atorvastatin, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof. A moreparticular statin is atorvastatin calcium salt. A further particularstatin is(E)-7-[4(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid (rosuvastatin), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a pro drug thereof. A preferable particularstatin is rosuvastatin calcium salt.

In an additional aspect of the invention, the compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof may be administered in association with an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof and/or a bile acid binderthereby avoiding a possible risk of excess of bile acids in colon causedby the inhibition of the ileal bile acid transport system. An excess ofbile acids in the visceral contents may cause diarrhoea. Thus, thepresent invention also provides a treatment of a possible side effectsuch as diarrhoea in patients during therapy comprising the compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof.

An HMG CoA-reductase inhibitor, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof will by its actiondecrease the endogenous cholesterol available for the bile acidsynthesis and have an additive effect in combination with the compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof on lipid lowering.

Suitable bile acid binders for such a combination therapy are resins,such as cholestyramine and cholestipol. One advantage is that the doseof bile acid binder might be kept lower than the therapeutic dose fortreatment of cholesterolaemia in single treatment comprising solely abile acid binder. By a low dose of bile acid binder any possible sideeffects caused by poor tolerance of the patient to the therapeutic dosecould also be avoided.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith a bile acid binder.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in simultaneous, sequential or separate administrationwith a bile acid binder.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of a bile acid binder.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in simultaneous, sequential or separate administrationwith a bile acid binder.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof and a bile acid binder, in association with apharmaceutically acceptable diluent or carrier.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid binder in association with apharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a bile acid binder.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereofand an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof and a bileacid binder.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof; in a    second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) a bile acid binder; in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof; in a    second unit dosage form;-   c) a bile acid binder; in a third unit dosage form; and-   d) container means for containing said first, second and third    dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof, in a    second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) a bile acid binder, in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof, in a    second unit dosage form; and-   c) a bile acid binder; in a third unit dosage form; and-   d) container means for containing said first, second and third    dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrag thereof, and an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the production of an IBAT inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a bile acidbinder, in the manufacture of a medicament for use in the production ofan IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof; and an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, and a bile acid binder, inthe manufacture of a medicament for use in the production of an IBATinhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the treatment of hyperlipidaemic conditions in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, a bile acidbinder, in the manufacture of a medicament for use in the treatment ofhyperlipidaemic conditions in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, and a bile acid binder, inthe manufacture of a medicament for use in the treatment ofhyperlipidaemic conditions in a warm-blooded animal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

According to a farther aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a bile acid binder, optionally together with apharmaceutically acceptable diluent or carrier to a warm-blooded animal,such as man in need of such therapeutic treatment.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptableexcipient, with the simultaneous, sequential or separate administrationof an effective amount of a bile acid binder, optionally together with apharmaceutically acceptable diluent or carrier to a warm-blooded aninal,such as man in need of such therapeutic treatment.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administrationone or more of the following agents selected from:

-   -   a CETP (cholesteryl ester transfer protein) inhibitor, for        example those referenced and described in WO 00/38725 page 7        line 22-page 10, line 17 which are incorporated herein by        reference;    -   a cholesterol absorption antagonist for example azetidinones        such as SCH 58235 and those described in U.S. Pat. No. 5,767,115        which are incorporated herein by reference;    -   a MTP (microsomal transfer protein) inibitor for example those        described in Science, 282, 751–54, 1998 which are incorporated        herein by reference;    -   a fibric acid derivative; for example clofibrate, gemfibrozil,        fenofibrate, ciprofibrate and bezafibrate;    -   a nicotinic acid derivative, for example, nicotinic acid        (niacin), acipimox and niceritrol;    -   a phytosterol compound for example stanols;    -   probucol;    -   an anti-obesity compound for example orlistat (EP 129,748) and        sibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);    -   an antihypertensive compound for example an angiotensin        converting enzyme inhibitor, an angiotensin II receptor        antagonist, an andrenergic blocker, an alpha andrenergic        blocker, a beta andrenergic blocker, a mixed alpha/beta        andrenergic blocker, an andrenergic stimulant, calcium channel        blocker, a diuretic or a vasodilator;    -   insulin;    -   sulphonylureas including glibenclamide, tolbutamide;    -   metformin; and/or    -   acarbose;        or a pharmaceutically acceptable salt, solvate, solvate of such        a salt or a prodrug thereof, optionally together with a        pharmaceutically acceptable diluent or carrier to a warm-blooded        animal, such as man in need of such therapeutic treatment.

Particular ACE inhibitors or pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof, including activemetabolites, which can be used in combination with a compound of formula(I) include but are not limited to, the following compounds: alacepril,alatriopril, altiopril calcium, ancovenin, benazepril, benazeprilhydrochloride, benazeprilat, benzoylcaptopril, captopril,captopril-cysteine, captopril-glutathione, ceranapril, ceranopril,ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid,enalapril, enalaprilat, enapril, epicaptopril, foroxymithine,fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinoprilsodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4,idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril,lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril,muracein A, muracein B, muracein C, pentopril, perindopril,perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride,quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride,spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocaprilhydrochloride, teprotide, trandolapril, trandolaprilat, utibapril,zabicipril, zabiciprilat, zofenopril and zofenoprilat. Preferred ACEinhibitors for use in the present invention are ramipril, ramiprilat,lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors foruses in the present invention are ramipril and ramiprilat.

Preferred angiotensin II antagonists, pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof for use incombination with a compound of formula (I) include, but are not limitedto, compounds: candesartan, candesartan cilexetil, losartan, valsartan,irbesartan, tasosartan, telmisartan and eprosartan. Particularlypreferred angiotensin II antagonists or pharmaceutically acceptablederivatives thereof for use in the present invention are candesartan andcandesartan cilexetil.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a PPAR alphaand/or gamma agonist, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/orgamma agonists, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are well known in the art. These includethe compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39,665, Expert Opinion on Therapeutic Patents, 10 (5), 623–634 (inparticular the compounds described in the patent applications listed onpage 634) and J Med Chem, 2000, 43, 527 which are all incorporatedherein by reference. Particularly a PPAR alpha and/or gamma agonistrefers to WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578,troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone,BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207,L-796449, L-165041 and GW 2433. Particularly a PPAR alpha and/or gammaagonist refers to(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoicacid and pharmaceutically acceptable salts thereof. Additional suitablePPAR alpha and/or gamma agonists are NN622/Ragaglitazar and BMS 298585.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof; in a first    unit dosage form;-   b) a PPAR alpha and/or gamma agonist, or a pharmaceutically    acceptable salt, solvate, solvate of such a salt or a prodrug    thereof; in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) a PPAR alpha and/or gamma agonist, or a pharmaceutically    acceptable salt, solvate, solvate of such a salt or a prodrug    thereof, in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a PPAR alphaand/or gamma agonist, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the production of an IBAT inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, a PPAR alphaand/or gamma agonist, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the treatment of hyperlipidaemic conditions in awarm-blooded animal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

In addition to their use in therapeutic medicine, the compounds offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, are also useful as pharmacologicaltools in the development and standardisation of in vitro and in vivotest systems for the evaluation of the effects of inhibitors of IBAT inlaboratory animals such as cats, dogs, rabbits, monkeys, rats and mice,as part of the search for new therapeutic agents.

Many of the intermediates described herein are novel and are thusprovided as a further feature of the invention. For example compounds offormula (IXa), (IXb), (Xa) and (Xb) show IBAT inhibitory activity whentested in the above referenced in vitro test assay and are thus claimedas a further feature of the invention.

Thus in a further feature of the invention, there is provided a compoundof formula (IXa), (IXb), (Xa) or (Xb), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

Therefore according to a further aspect of the invention there isprovided a pharmaceutical composition which comprises a compound offormula (IXa), (IXb), (Xa) or (Xb), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in association with a pharmaceutically-acceptable diluentor carrier.

According to an additional aspect of the present invention there isprovided a compound of the formula (IXa), (IXb), (Xa) or (Xb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore for use in a method ofprophylactic or therapeutic treatment of a warm-blooded animal, such asman.

Thus according to this aspect of the invention there is provided acompound of the formula (IXa), (IXb), (Xa) and (Xb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore for use as a medicament.

According to another feature of the invention there is provided the useof a compound of the formula (IXa), (IXb), (Xa) or (Xb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof as defined hereinbefore in the manufacture of amedicament for use in the production of an IBAT inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (IXa), (IXb), (Xa) or (Xb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof as defined hereinbefore in the manufacture of amedicament for use in the treatment of hyperlipidaemic conditions in awarm-blooded animal, such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (IXa), (IXb), (Xa) or (Xb), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (IXa), (IXb), (Xa) or (Xb), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated in the following non limitingexamples, in which standard techniques known to the skilled chemist andtechniques analogous to those described in these examples may be usedwhere appropriate, and in which, unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and    work up procedures were carried out after removal of residual solids    such as drying agents by filtration;-   (ii) all reactions were carried out under an inert atmosphere at    ambient temperature, typically in the range 18–25° C., with solvents    of HPLC grade under anhydrous conditions, unless otherwise stated;-   (iii) column chromatography (by the flash procedure) was performed    on Silica gel 40–63 μm (Merck);-   (iv) yields are given for illustration only and are not necessarily    the maximum attainable;-   (v) the structures of the end products of the formula (I) were    generally confirmed by nuclear (generally proton) magnetic resonance    (NMR) and mass spectral techniques; magnetic resonance chemical    shift values were measured in deuterated CD₃OD (unless otherwise    stated) on the delta scale (ppm downfield from tetramethylsilane);    proton data is quoted unless otherwise stated; spectra were recorded    on a Varian Mercury-300 MHz, Varian Unity plus-400 MHz, Varian Unity    plus-600 MHz or on Varian Inova-500 MHz spectrometer; and peak    multiplicities are shown as follows: s, singlet; d, doublet; dd,    double doublet; t, triplet; tt, triple triplet; q, quartet; tq,    triple quartet; m, multiplet; br, broad; LCMS were recorded on a    Waters ZMD, LC column xTerra MS C₈(Waters), detection with a HP 1100    MS-detector diode array equipped; mass spectra (MS) (loop) were    recorded on VG Platform II (Fisons Instruments) with a HP-1100    MS-detector diode array equipped; unless otherwise stated the mass    ion quoted is (MH⁺);-   (vi) unless further details are specified in the text, analytical    high performance liquid chromatography (HPLC) was performed on Prep    LC 2000 (Waters), Kromasil C₈, 7 μm, (Akzo Nobel); MeCN and    de-ionised water 100 mM ammonium acetate as mobile phases, with    suitable composition;-   (vii) intermediates were not generally fully characterised and    purity was assessed by thin layer chromatography (TLC), HPLC,    infra-red (IR), MS or NMR analysis;-   (viii) where solutions were dried sodium sulphate was the drying    agent;-   (ix) where an “ISOLUTE” column is referred to, this means a column    containing 2 g of silica, the silica being contained in a 6 ml    disposable syringe and supported by a porous disc of 54 Å pore size,    obtained from International Sorbent Technology under the name    “ISOLUTE”; “ISOLUTE” is a registered trade mark;-   (x) the following abbreviations may be used hereinbefore or    hereinafter:

DCM dichloromethane; DMF N,N-dimethylformamide; TFA trifluoroaceticacid; TBTU o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate; EtOAc ethyl acetate; and MeCN acetonitrile.

Example 11,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 2; 0.020 g, 3.71*10⁻⁵ mol) in DCM (4 ml) was added(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 5; 0.013g, 4.82*10⁻⁵ mol) and N-methylmorpholine (0.015 ml, 1.48*10⁻⁴ mol). Themixture was stirred for 5 min and then TBTU (0.015 g, 4.82*10⁻⁵ mol) wasadded. The reaction mixture was stirred overnight and then TFA (1.5 ml)was added. After 1 hour, the solution was diluted with toluene, beforethe solvent was removed under reduced pressure. The residue was purifiedby preparative HPLC using an MeCN/ammonium acetate buffer as eluent. andfreeze-dried, to give the title compound in 0.026 g (96%) as a whitesolid. NMR (400 MHz, DMSO-d6) 0.60–0.80 (m, 6H), 0.80–1.60 (m, 12H),3.30 (dd (AB), 1H), 3.45 (dd (AB), 1H), 3.85 (brs, 2H), 4.70 (d (AB),1H), 4.75 (d (AB), 1H), 5.60 (d, 1H), 6.90–7.50 (m, 12H), 8.00–8.10(m,1H). 8.55 (d, 1H).

Example 21,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 3; 0.016 g, 3.16*10⁻⁵ mol) in DCM (4 ml) was added(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 5; 0.012g, 4.54*10⁻⁵ mol) and N-methylmorpholine (0.015 ml, 1.48*10⁻⁴ mol). Themixture was stirred for 5 min and then TBTU (0.015 g, 4.82*10⁻⁵ mol) wasadded. The reaction mixture was stirred overnight and then TFA (1.5 ml)was added. After 1 hour, the solution was diluted with toluene, beforethe solvent was removed under reduced pressure. The residue was purifiedby preparative HPLC using an MeCN/ammonium acetate buffer as eluent andfreeze-dried, to give the title compound in 0.018 g (82%) as a whitesolid. NMR (400 MHz, DMSO-d6) 0.65–0.80 (m, 6H), 0.85–1.60 (m, 12H),2.10 (s, 3H), 3.65 (dd (AB), 1H), 3.75 (dd (AB), 1H), 3.85 (brs, 2H),4.65 (d (AB), 1H), 4.75 (d (AB), 1H), 5.60 (d, 1H), 6.55 (s, 1H),6.90–7.50 (m, 11H), 8.45 (d, 1H), 8.50–8.60 (m, 1H).

Example 31,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 2; 0.050 g, 9.27*10⁻⁵ mol) in DMF (6 ml) was added2-{[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acid(Method 6; 0.033 g, 1.20*10⁻⁴ mol) and N-methylmorpholine (0.041 ml,3.72*10⁻⁴ mol). The mixture was stirred for 10 min and then TBTU (0.039g, 1.21*10⁻⁴ mol) was added. The reaction mixture was stirred overnightand the solvent was removed under reduced pressure. The residue waspurified by preparative HPLC using an MeCN/ammonium acetate buffer aseluent and freeze-dried, to give the title compound in 0.039 g (53%) asa white solid. NMR (400 MHz, DMSO-d6) 0.60–0.80 (m, 6H), 0.80–1.60 (m,12H), 2.40–2.60 (m, 2H), 3.10‘3.50 (m, 2H), 3.85 (brs, 2H), 4.70 (d(AB), 1H), 4.75 (d (AB), 1H), 5.25 (d, 1H), 6.70 (s, 1H), 6.75 (s, 1H),6.85–7.80 (m, 10H), 8.15–8.25 (m, 1H). 8.45 (d, 1H), 9.40 (brs, 1H).

Example 41,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 3; 0.050 g, 0.099 mmol), t-butylN-[(2R)-2-amino-2-phenylethanoyl]-o-(t-butyl)-L-serinate (Method 14;0.042 g, 0.120 mmol) and N-methylmorpholine (0.033 ml, 0.299 mmol) inDCM (4 ml) was stirred at RT for 10 min, after which TBTU (0.041 g,0.128 mmol)) was added. After 8 h, the conversion was completed; m/z:839.7. TFA (2 ml) was added and the reaction mixture was stirred for 12hours. The solution was transferred to a separating funnel and washedtwice with water and then concentrated. The residue was purified bypreparative HPLC using a gradient of 40–60% MeCN in 0.1M ammoniumacetate buffer as eluent. The title compound was obtained in 0.045 g(63%) as a white solid. NMR (400 MHz, DMSO-d₆): 0.60–0.80 (6H, m),0.85–1.60 (12H, m), 2.10 (3H, s), 3.40–3.65 (2H, m), 3.85 (2H, brs),4.10–4.20 (1H, m), 4.70 (1H, d(AB)), 4.75 (1H, d(AB)), 5.70 (1H, d),6.60 (1H, s), 6.85–7.50 (12H, m), 8.50 (1H, d), 8.60 (1H, d); m/z:839.7.

Example 51,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 0.055 g, 0.086 mmol), L-alanine, 1,1-dimethylethyl ester,hydrochloride (0.017 g, 0.098 mmol) and N-methylmorpholine (0.028 ml,0.254 mmol) in DCM (5 ml) was stirred at RT for 10 min, after which TBTU(0.033 g, 0.103 mmol) was added. After 16 h the conversion was complete;m/z: 767.4. TFA (2.5 ml) was added and the reaction mixture was stirredfor 2 hours. The solution was diluted with toluene and thenconcentrated. The residue was purified by preparative HPLC using agradient of 40–60% MeCN in 0.1M ammonium acetate buffer as eluent. Thetitle compound was obtained in 0.044 g (72%) as a white solid. NMR (400MHz): 0.70–0.85 (6H, m), 0.90–1.70 (12H, m), 1.30 (3H, d), 2.10 (3H, s),3.95 (2H, brs), 4.25–4.40 (1H, m), 4.60 (1H, d(AB)), 4.65 (1H, d(AB)),5.60 (1H, s), 6.60 (1H, s), 6.95–7.50 (11H, m); m/z: 767.4.

Example 61,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 0.055 g, 0.086 mmol), butanoic acid, 2-amino-,1,1-dimethylethyl ester, hydrochloride, (2S)-(0.020 g, 0.102 mmol) andN-methylmorpholine (0.035 ml, 0.316 mmol) in DCM (5 ml) was stirred atRT for 10 min, after which TBTU (0.036 g, 0.112 mmol) was added. After19 h additional butanoic acid, 2-amino-, 1,1-dimethylethyl ester,hydrochloride, (2S)-(0.020 g, 0.102 mmol), N-methylmorpholine (0.035 ml,0.316 mmol) and TBTU (0.036 g, 0.112 mmol) were added. After 68 h, theconversion was completed; m/z: 781.5. TFA (2 ml) was added and thereaction mixture was stirred for 7 h and then additional TFA (2 ml) wasadded. After 18 h the reaction was completed. The solution wastransferred to a separating funnel and washed twice with water and thenconcentrated. The residue was purified by preparative HPLC using agradient of 40–60% MeCN in 0.1M ammonium acetate buffer as eluent. Thetitle compound was obtained in 0.026 g (41%) as a white solid. NMR (400MHz, DMSO-d₆): 0.65 (3H, t), 0.65–0.80 (6H, m), 0.85–1.75 (14H, m), 2.10(3H, s), 3.80 (2H, brs), 3.95–4.10 (1H, m), 4.65 (1H, d(AB)), 4.75 (1H,d(AB)), 5.65 (1H, d), 6.55 (1H, s), 6.85–7.50 (12H, m), 8.50 (1H, d),8.60 (1H, d); m/z 781.5.

Example 71,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 0.055 g, 0.086 mmol), S-methyl-L-cysteine tert-butyl ester(Pestic. Sci.; EN; 45; 4; 1995; 357–362; 0.020 g, 0.105 mmol) andN-methylmorpholine (0.035 ml, 0.317 mmol) in DCM (5 ml) was stirred atRT for 10 min, after which TBTU (0.036 g, 0.112 mmol) was added. After19 h additional S-methyl-L-cysteine tert-butyl ester (0.020 g, 0.105mmol), N-methylmorpholine (0.035 ml, 0.317 mmol) and TBTU (0.036 g,0.112 mmol) were added. After 68 h the conversion was complete; m/z:811.6 (M-1)⁻. TFA (1.5 ml) was added and the reaction mixture wasstirred for 7 h and additional TFA (1.5 ml) was added. After 18 h thereaction was complete. The solution was transferred to a separatingfunnel and washed twice with water and then concentrated. The residuewas purified by preparative HPLC using a gradient of 40–60% MeCN in 0.1Mammonium acetate buffer as eluent. The title compound was obtained in0.042 g (65%) as a white solid. NMR (400 MHz, DMSO-d₆): 0.65–0.80 (6H,m), 0.85–1.60 (12H, m), 1.85 (3H, s), 2.10 (3H, s), 2.60–2.80 (2H, m),3.80 (2H, brs), 4.20–4.35 (1H, m), 4.65 (1H, d(AB)), 4.75 (1H, d(AB)),5.65 (1H, d), 6.55 (1H, s), 6.85–7.50 (12H, m), 8.45 (1H, d), 8.65 (1H,d).

Example 81,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-carbamoylethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

N-Methylmorpholine (0.034 ml, 0.314 mmol), TBTU (0.033 g, 0.103 mmol)and L-asparagine, 1,1-dimethylethyl ester, monohydrochloride (0.021 g,0.093 mmol) was successively added to a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 0.050 g, 0.078 mmol) in DCM (5 ml). After 2 h there werestill starting material left and additional N-methylmorpholine (0.035ml, 0.314 mmol) and TBTU (0.033 g, 0.103 mmol) were added. After 12 hthe conversion was complete; m/z: 810.5. The solution was diluted withwater (˜5 ml) and then extracted three times with ether. The combinedorganic phases was dried over magnesium sulphate and concentrated. Theresidue was dissolved in a mixture of DCM (5 ml) and TFA (2.5 ml) andthe solution was stirred for 21 hours. The solution was transferred to aseparating funnel and washed with water and then concentrated. Theresidue was purified by preparative HPLC using a gradient of 40–60% MeCNin 0.1M ammonium acetate buffer as eluent. The title compound wasobtained in 0.022 g (37%) as a white solid. NMR (400 MHz, DMSO-d₆):0.60–0.80 (6H, m), 0.80–1.60 (12H, m), 2.10 (3H, s), 2.25–2.70 (2H, m),3.80 (2H, brs), 4.35–4.45 (1H, m), 4.65 (1H, d(AB)), 4.75 (1H, d(AB)),5.60 (1H, d), 6.55 (1H, s), 6.70–7.60 (14H, m), 8.45 (1H, d), 8.55–8.70(1H, m); m/z 810.5.

Example 91,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepineammonium salt

The title compound was synthesized using the procedure of Example 3starting from1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 3; 43 mg, 0.085 mmol). The solvent was evaporated after 3 hoursand the crude product was purified by preparative HPLC (C8 column,50×250 mm) using a gradient (40/60 to 60/40) of MeCN/0.1M amnmoniumacetate buffer as eluent. Lyophilization yielded 38 mg (57% yield) ofthe title compound. NMR (400 MHz): 0.8 (t, 6H), 1.0–1.2 (m, 6H),1.25–1.4 (m, 2H), 1.4–1.5 (m, 2H), 1.55–1.7 (m, 2H), 2.1 (s, 3H),2.8–3.0 (m, 2H), 3.55–3.7 (m, 2H), 3.95 (brs, 2H), 4.6 (ABq, 2H), 5.35(s, 1H), 6.6 (s, 1H), 6.75 (d, 2H), 7.05 (t, 1H) 7.15–7.4 (m, 7H), 8.15(t, 1H); m/z: 763.

Example 101,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 18; 50 mg, 0.076 mmol) was dissolved in DCM (4 ml). Glycinetert-butyl ester (12 mg, 0.091 mmol), 2,6-lutidine (20 μl, 0.15 mmol)and TBTU (30 mg, 0.091 mmol) were added successively. After 3 h DMF (2ml) was added and a clear solution was obtained. Glycine tert-butylester (0.04 mmol), 2,6-lutidine (0.15 mmol) and TBTU (2×0.03 mmol) wereadded and the mixture was stirred for an additional 3 h. The reactionrnixture was concentrated and then extracted between aqueous KHSO₄(0.05M, pH=1) and EtOAc (2×20 ml). The organic phase was washed withbrine, dried and concentrated to yield an oil containing the tert-butylester of the title compound. M/z: 769 and 786 (M+18 (NH₄ ⁺)). DCM (4 ml)and TFA (1.5 ml) were added. The mixture was stirred for 2 hours and wasthen concentrated and purified by preparative HPLC on a C8 column(50×250 mm) using a gradient (20/80 to 50/50) of MeCN/0.01M ammoniumacetate buffer as eluent. Lyophilization yielded the title compound in52% (28 mg). NMR (400 MHz) 0.8 (t, 6H), 1.0–1.2 (m, 6H), 1.25–1.4 (m,2H), 1.4–1.5 (m, 2H), 1.55–1.7 (m, 2H), 2.1 (s, 3H), 3.9 (ABq, 2H), 3.95(brs, 2H), 4.6 (ABq, 2H), 5.45 (s, 1H), 6.6 (s, 1H), 6.75 (d, 2H), 7.05(t, 1H) 7.15–7.4 (m, 7H); m/z: 730 (M+18 (NH₄ ⁺).

Example 111,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R-)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

The title compound was synthesized by the procedure described in Example10 starting from1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 18; 50 mg, 0.076 mmol) and tert-butyl L-alarinatehydrochloride. The intermediate tert-butyl ester of the title compoundwas confirmed. M/z: 783 and 800 (M+18 (NH₄ ⁻)). Hydrolysis andpurification by preparative HPLC yielded the title compound in 20 mg(37% yield). NMR (400 MHz) 0.8 (t, 6H), 1.0–1.2 (m, 6H), 1.25–1.4 (m,2H), 1.3 (d, 3H), 1.4–1.5 (m, 2H), 1.55–1.7 (m, 2H), 2.1 (s, 3H), 3.95(brs, 2H), 4.35 (q, 1H), 4.6 (ABq, 2H), 5.45 (s, 1H), 6.6 (s, 1H), 6.75(d, 2H), 7.05 (t, 1H) 7.15–7.4 (m, 7H1); m/z: 744.

Example 121,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]-4-hydroxbenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

The title compound was synthesized by the procedure described in Example10 starting from1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 18; 50 mg, 0.076 mmol) and tert-butyl o-(tert-butyl)-L-serinatehydrochloride. The intermediate ester was confirmed; m/z: 755.Hydrolysis and purification by preparative HPLC yielded the titlecompound in 19 mg (33% yield). M/z: 743 (M+1). NMR (400 MHz): 0.8 (t,6H), 1.0–1.2 (m, 6H), 1.25–1.4 (m, 2H), 1.4–1.5 (m, 2H), 1.55–1.7 (m,2H), 2.1 (s, 3H), 3.65–3.8 (m, 2H), 3.95 (brs, 2H), 4.33 (t, 1H), 4.6(ABq, 2H), 5.5 (s, 1H), 6.6 (s, 1H), 6.75 (d, 2H), 7.05 (t, 1H) 7.15–7.4(m, 7H).

Example 131,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepineammonium salt

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol) was dissolved in 3 ml DCM.Tetrabutylammonium taurine (88 mg, 0.236 mmol) was added and the mixturewas stirred for 30 min. TBTU (30 mg, 0.093 mmol) was added and themixture was stirred overnight. The solution was concentrated andpurified by preparative HPLC using a C8 column (50×250 mm). A gradient(20/80 to 60/40) of MeCN/0.1M ammonium acetate buffer was used aseluent. Lyophilization yielded 43 mg of a product mixture, which wasfurther purified by flash chromatography (5 g) using a gradient of 3–20%MeOH in DCM as eluent. The fractions containing the title compound werecollected and concentrated. MeOH and water were added and lyophilizationyielded 17 mg (29% yield). NMR (400 MHz) 0.8 (t, 6H), 1.0–1.2 (m, 6H),1.25–1.4 (m, 2H), 1.4–1.5 (m, 2H), 1.55–1.7 (m, 2H), 2.1 (s, 3H),2.85–3.0 (m, 2H), 3.5–3.7 (m, 2H), 3.95 (brs, 2H), 4.6 (ABq 2H), 5.45(s, 1H), 6.6 (s, 1H), 7.05 (t, 1H) 7.15–7.45 (m, 10H); m/z: 747.

Example 141,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol) was dissolved in 1 ml DMF and 1 ml DCM.o-tert-Butyl-(L)-threonine tert-butyl ester (22 mg, 0.095 mmol) andN-methylmorpholine (17 μl, 0.154 mmol) were added and the mixture wasstirred for 20 min. TBTU (30 mg, 0.093 mmol) was added and the solutionwas stirred for 2 hours and concentrated. DCM (20 ml) was added and thesolution was washed with 10 ml brine, dried and concentrated to 3 ml.The intermediate ester was confirmed; m/z: 853. TFA (0.5 ml) was addedand the solution was stirred overnight. Additionally 0.5 ml TFA wasadded and after 3 h the mixture was concentrated and purified bypreparative HPLC on a C8 column (50×250 mm). A gradient (20/80 to 60/40)of MeCN/0.1M ammonium acetate buffer was used as eluent. Lyophilizationgave the title compound in 61% yield (36 mg). NMR (400 MHz) 0.8 (t, 6H),0.9 (d, 3H), 1.0–1.2 (m, 6H), 1.25–1.4 (m, 2H), 1.4–1.5 (m, 2H),1.55–1.7 (m, 2H), 2.1 (s, 3H), 3.95 (brs, 2H), 4.15–4.25 (m, 1H), 4.35(d, 1H), 4.6 (ABq, 2H), 5.65 (s, 1H), 6.6 (s, 1H), 7.05 (t, 1H), 7.1 (d,2H), 7.15–7.4 (m, 6H), 7.5 (d, 2H); m/z: 7.41.

Example 151,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol) was dissolved in 2 ml DMF. tert-Butyl(L)-valinate (20 mg, 0.095 mmol) and N-methylmorpholine (17 μl, 0.154mmol) were added and the mixture was stirred for 20 min. TBTU (30 mg,0.093 mmol) was added and the solution was stirred overnight. AdditionalN-methylmorpholine (8 μl, 0.078 mmol) and TBTU (3×5 mg, 0.047 mmol) wereadded and the mixture was stirred overnight and concentrated. Theresidue was purified by flash chromatography (2 g) using EtOAc:hexane(3:7) as eluent. The collected fraction was washed with 5% NaHCO₃ (10ml), 0.1M KHSO₄ (15 ml) and brine before it was dried and concentrated.The intermediate tert-butyl ester of the title compound was confirmed;m/z: 812 (M+18 (NH₄ ⁺)). DCM (4 ml) and TFA (1.5 ml) were added and themixture was stirred overnight, concentrated and purified by preparativeHPLC on a C8 column (50×25 mm). A gradient (20/80 to 60/40) of MeCN/0.1Mammonium acetate buffer was used as eluent. Lyophilization gave thetitle compound in 31% yield (18 mg). NMR (400 MHz) 0.65–0.85 (m, 12H),0.95–1.2 (m, 6H), 1.25–1.4 (m, 2H), 1.4–1.5 (m, 2H), 1.55–1.7 (m, 2H),2.02–2.2 (m, 1H), 2.1 (s, 3H), 3.95 (brs, 2H), 4.3 (d, 1H), 4.6 (ABq,2H), 5.65 (s, 1H), 6.6 (s, 1H), 7.05 (t, 1H), 7.2 (d, 2H), 7.25–7.4 (m,6H), 7.5 (d, 2H); m/z: 739.

Example 161,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-3-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

The title compound was synthesized by the procedure given in Example 15starting from1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol) and tert-butyl (L)-leucinate (21 mg,0.095 mmol). The DMF was removed and 20 ml EtOAc was added and washedwith NaHCO₃ (5%, 10 ml), 0.1M KHSO₄ (15 ml) and brine before it wasdried and concentrated. The resulting residue was purified by flashchromatography as described. The intermediate tert-butyl ester of thetitle compound was confirmed; m/z: 826 (M+18 (NH₄ ⁺)). Hydrolysis andpurification by preparative HPLC gave the title compound in 21% yield(12 mg). NMR (400 MHz) 0.7 (dd, 6H), 0.75–0.85 (m, 6H), 0.95–1.2 (m,6H), 1.25–1.7 (m, 9H), 2.1 (s, 3H), 3.95 (brs, 2H), 4.3–4.4 (m, 1H), 4.6(ABq, 2H), 5.55 (s, 1H), 6.6 (s, 1H), 7.05 (t, 1H), 7.2 (d, 2H),7.25–7.4 (m, 6H) 7.5 (d, 2H; m/z: 753.

Example 171,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(1-(S)-1-carboxy-2-(S)-2-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

The title compound was synthesized by the procedure given in Example 15starting from1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol) and tert-butyl (L)-iso-leucinate (21 mg,0.095 mmol). The DMF was removed and 20 ml EtOAc was added and washedwith NaHCO₃ (5%, 10 ml), 0.1M KHSO₄ (15 ml) and brine before it wasdried and evaporated. No purification by flash chromatography wasperformed. The intermediate tert-butyl ester of the title compound wasconfirmed; m/z: 809. Hydrolysis and purification by preparative HPLCgave the title compound in 37% yield (22 mg). NMR (400 MHz) 0.65–1.4 (m,22H), 1.4–1.5 (m, 2H), 1.5–1.7 (m, 2H), 1.75–1.85 (m, 1H), 2.1 (s, 3H),3.95 (brs, 2H), 4.25 (d, 1H), 4.6 (ABq, 2H), 5.6 (s, 1H), 6.6 (s, 1H),7.05 (t, 1H), 7.2 (d, 2H), 7.25–7.4 (m, 6H), 7.45 (d, 2H); m/z: 753.

Example 181,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 3; 295 mg, 0.58 mmol) was dissolved in 10 ml DCM.4-(1-(R)-t-Butoxycarbonyl-1-aminomethyl)phenol (Method 7; 160 mg, 0.72mmol), 2,6-lutidine (140 μl, 1.20 mmol) and TBTU (230 mg, 0.72 mmol)were added successively. The mixture was stirred for 3 h. Additionally4-(1-(R)-t-butoxycarbonyl-1-aminomethyl)phenol (10 mg, 0.04 mmol) wasadded and stirring was continued for 2 h. DCM (20 ml) was added and thesolution was washed with NaHCO₃ (5%, 20 ml), KHSO₄ (0.3M; 20 ml), brine(20 ml) before it was dried and concentrated to a volume of 10 ml. Thetert-butyl ester of the title compound was confirmed; m/z: 729 (M+18(NH₄ ⁺)). TFA (1.3 ml) was added and the mixture was stirred for 4.5 hand concentrated. The crude product was purified by preparative HPLCusing a C8 column (5×500 mm) and a gradient (40/60 to 70/30 over 40 min)of MeCN/0.1M ammonium acetate buffer as eluent. Lyophilization yieldedthe title compound in 77.5% (302 mg). NMR (400 MHz) 0.8 (t, 6H), 1.0–1.2(m, 6H), 1.25–1.4 (m, 2H), 1.4–1.5 (m, 2H), 1.55–1.7 (m, 2H), 2.1 (s,3H), 3.95 (brs, 2H), 4.6 (ABq, 2H), 5.3 (s, 1H), 6.6 (s, 1H), 6.75 (d,2H), 7.05 (t, 1H) 7.15–7.4 (m, 7H); m/z: 673 (M+18 (NH₄ ⁺)).

Example 191,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-4-aminobutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N-[(S)-1-(t-butoxycarbonyl)-4-(benzyloxycarbonylamino)butyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 8; 0.006 mg) was dissolved in DCM (0.2 ml), TFA (1 ml) was addedand the reaction mixture was stirred at room temperature for 1 hour. DCMand TFA were removed at reduced pressure and the residue was purified bypreparative HPLC using MeCN/NH4⁺ buffer 50/50 as eluent. Theacetonitrile was evaporated and lyophilisation gave the title compoundin 37% yield (21.9 mg). M/z: 754.4 and 752.4 (M−H)⁻.

Example 201,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N-[(S)-1-carboxy-4-(benzyloxycarbonylamino)butyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N-[(S)-1-(t-butoxycarbonyl)-4-(benzyloxycarbonylamino)butyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 8; 0.006 mg) was dissolved in DCM (0.1 ml), TFA (0.15 ml) wasadded and the reaction mixture was stirred at room temperature for 1hour. DCM and TFA were removed at reduced pressure and the residue waspurified by preparative HPLC using MeCN/NH4⁺ buffer 55/45 as eluent. Theacetonitrile was evaporated and lyophilisation gave the title compoundin 35% yield (2 mg). M/z: 888.7 and 886.7 (M−H)⁻.

Example 211,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-((S)-2-carboxypyrrolidin-1-ylcarbonyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-2-(t-butoxycarbonyl)pyrrolidin-1-ylcarbonyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 10; 41 mg, 0.052 mmol) was dissolved in DCM:TFA 4:1 (3 ml) andstirred for 3 hours. The reaction mixture was evaporated under reducedpressure. The residue was purified by preparative HPLC using anacetonitrile/ammonium acetate buffer gradient (5/95 to 100/0) as eluent.26.5 mg (70%) of the title compound was obtained after lyophilisation.M/z 737.3034.

Example 221,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)-N-methylcarbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

The title compound was synthesized from1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{R)-α-[N-(t-butoxycarbonylmethyl)-N-methylcarbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 11) by the method of Example 21. NMR (500 MHz, 2 rotamers 3:1mixture): Major rotamer: 0.8 (brt, 6H), 1.0–1.24 (m, 6H), 1.25–1.4 (m,2H), 1.4–1.51 (m, 2H), 1.56–1.68 (m, 2H), 2.09 (s, 3H), 3.0 (s, 3H)3.75–4.21 (m, 4H), 4.60 (ABq, 2H), 6.01 (s, 1H), 6.58 (s, 1H), 7.05 (t,1H), 7.16–7.28 (m, 3H), 7.3–7.45 (m, 5H), 7.48 (brd, 2H) additionalpeaks from the minor rotamer at 2.14 (s), 3.0 (s), 4.56 (Abq), 5.81 (s),6.61 (brs); m/z 711.4.

Example 231,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(1-(R)-2-(R)-1-carboxy-1-hydroxyprop-2-yl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

The title compound was synthesized from1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N-[1-(R)-2-(R)-1-(t-butoxycarbonyl)-1-hydroxy-prop-2-yl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 12) by the method of Example 21. M/z 741.3.

Example 241,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(sulphomethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepineammonium salt

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol), aminomethanesulfonic acid (15 mg, 0.088mmol) and N-methylmorpholine (17.2 μl, 0.156 mmol) were dissolved in DMF(2 ml). Tetrabutylammoniumhydrogensulfate (35 mg, 0.103 mmol) was addedand the mixture was heated for 15 minutes at 60° C. After removingheating TBTU (45 mg, 0.14 mmol) was added. The reaction mixture wasstirred in room temperature 40 minutes then 60° C. for one hour. Afterbeing stirred overnight 35 mg TBTU was added. After 6 hours 29 mg TBTUin small portions was added and the reaction mixture was stirredovernight. The mixture was evaporated under reduced pressure. Theproduct was purified using preparative HPLC using anacetonitrile/ammonium acetate buffer gradient (5/95 to 100/0) as eluent.To give 10 mg (17%) of the title compound as a ammonium salt. NMR (600MHz) 0.77 (brt, 6H), 0.97–1.22 (m, 6H), 1.24–1.48 (m, 4H), 1.51–1.68 (m2H), 2.08 (s, 3H), 3.7–4.18 (m, 2H), 4.24 (d, 1H), 4.39 (d, 1H), 4.62(ABq, 2H), 5.62 (s, 1H), 6.58 (brs, 1H), 7.02 (brt, 1H), 7.14–7.23 (m,2H), 7.24–7.36 (m, 6H), 7.45 (d, 2H),; m/z 732.9.

Example 251,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxyl]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(t-butoxycarbonyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 9; 762 mg, 1.09 mmol) was dissolved in a mixture of TFA (6.65ml) and triethylsilane (0.350 ml). The reaction mixture was stirred forone hour and then evaporated under reduced pressure to give the titlecompound in a quantitative yield (714 mg). NMR (500 MHz): 0.8 (brt, 6H),0.96–1.25 (m, 6H), 1.25–1.4 (m, 2H), 1.42–1.51 (m, 2H), 1.57–1.69 (m,2H), 2.11 (s, 3H), 3.8–4.15 (m, 2H), 4.66 (ABq, 2H), 5.49–5.53 (m, 1H),6.61 (s, 1H), 7.06 (t, 1H), 7.18–7.26 (m, 2H), 7.28–7.45 (m, 8H), 8.35(d, NH); m/z 640.2.

Example 261,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 18; 100 mg, 0.152 mmol) was dissolved in 3 ml DMF.o-tert-Butyl-(L)-threonine tert-butyl ester (50 mg, 0.216 mmol) andN-methylmorpholine (34 μl, 0.309 mmol) were added and the mixture wasstirred for 5 min. TBTU (60 mg, 0.1 87 mmol) was added and the solutionwas stirred for 30 min. Formic acid (1–2 drops) was added and themixture was extracted between EtOAc and water. The aqueous phase waswashed with EtOAc and the combined organic phases were washed with 2%NaHCO₃, brine, dried and concentrated. The intermediate t-butyl ester ofthe title compound was confirmed; m/z: 869. DCM (3 ml) and TFA (0.5 ml)were added and the solution was stirred overnight. The mixture wasconcentrated and purified by preparative HPLC on a C8 column (50×250mm). A gradient (20/80 to 50/50) of MeCN/0.1M ammonium acetate bufferwas used as eluent. Lyophilization gave the title compound in 61% yield(71 mg). NMR (400 MHZ) 0.78 (t, 6H), 0.93 (d, 3H), 1.0–1.22 (m, 6H),1.25–1.14 (m, 2H), 1.4–1.52 (m, 2H), 1.55–1.7 (m, 2H), 2.1 (s, 3H), 3.95(brs, 2H), 4.18–4.25 (m, 1H), 4.35 (d, 1H), 4.63 (ABq, 2H), 5.53 (s,1H), 6.57 (s, 1H), 6.75 (d, 2H), 7.03 (t, 1H), 7.2 (d, 2H), 7.23–7.37(m, 5H); m/z: 757.

Example 271,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

The title compound was synthesized by the procedure described in Example26 starting from1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 18; 70 mg, 0.108 mmol) and tert-butyl (L)-valinate (31 mg,0.148 mmol). The intermediate tert-butyl ester of the title compound wasconfirmed. M/z: 811. Hydrolysis and purification by preparative HPLCyielded the title compound in 56 mg (69% yield). NMR (400 MHz) 0.7–0.75(m, 16H), 0.79 (t, 6H), 0.96–1.24 (m, 6H), 1.25–1.4 (m, 2H), 1.4–1.5 (m,2H), 1.54–1.7 (m, 2H), 2.0–2.2 (m, 1H), 2.1 (s, 3H), 3.95 (brs, 2H),4.22 (d, 1H), 4.6 (ABq, 2H), 5.54 (s, 1H), 6.58 (s, 1H), 6.75 (d, 2H),7.03 (t, 1H), 7.2 (d, 2H), 7.23–7.37 (m, 5H); m/z: 7.55.

Example 281,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-trahydro-1,2,5-benzothiadiazepine

The title compound was synthesized by the procedure described in Example26 starting from1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 18; 36 mg, 0.054 mmol) and tert-butyl (L)-norvalinatehydrochloride (16 mg, 0.076 mmol). The intermediate tert-butyl ester ofthe title compound was confirmed. M/z: 811. Hydrolysis and purificationby preparative HPLC yielded the title compound in 23 mg (56% yield). NMR(400 MHz) 0.7–0.85 (m, 9H), 0.97–1.22 (m, 8H), 1.25–1.4 (m, 2H), 1.4–1.5(m, 2H), 1.5–1.8 (m, 4H), 2.1 (s, 3H), 3.95 (brs, 2H), 4.27 (dd, 1H),4.6 (ABq, 2H), 5.45 (s, 1H), 6.58 (s, 1H), 6.75 (d, 2H), 7.03 (t, 1H),7.19 (d, 2H), 7.23–7.37 (m, 5H); m/z: 755.

Example 291,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,25-benzothiadiazepine

A solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 18; 0.075 g, 0.114 mmol), butanoic acid, 2-amino-,1,1-dimethylethyl ester, hydrochloride, (2S)-(0.031 g, 0.160 mmol) andN-methylmorpholine (0.050 ml, 0.457 mmol) in DMF (4 ml) was stirred atRT for 10 min, after which TBTU (0.048 g, 0.149 mmol) was added. After 1h, the conversion to the ester was complete. M/z: 797.4. The solutionwas diluted with toluene and then concentrated. The residue wasdissolved in a mixture of DCM (5 ml) and TFA (2 ml) and the mixture wasstirred for 7 h. The solvent was removed under reduced pressure. Theresidue was purified by preparative HPLC using a gradient of 20–60% MeCNin 0.1M ammonium acetate buffer as eluent. The title compound wasobtained in 0.056 g (66%) as a white solid. NMR (400 MHz, DMSO-d₆): 0.70(3H, t), 0.70–0.80 (6H, m), 0.85–1.75 (14H, m), 2.10 (3H, s), 3.80 (2H,brs), 4.00–4.15 (1H, m), 4.65 (1H, d(AB)), 4.70 (1H, d(AB)), 5.50 (1H,d), 6.60 (1H, s), 6.65–7.40 (11H, m), 8.35 (1H, d), 8.50 (1H, d) 9.40(1H, brs).

Example 301,1-Dioxo-3,3-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example18, 0.075 g, 0.114 mmol), S-methyl-L-cysteine tert-butyl ester (Pestic.Sci.; EN; 45; 4; 1995; 357–362; 0.031 g, 0.160 mmol) andN-methylmorpholine (0.050 ml, 0.457 mmol) in DMF (4 ml) was stirred atRT for 10 min, after which TBTU (0.048 g, 0.149 mmol) was added. After 1h, the conversion to the ester was complete. M/z: 829.5. The reactionmixture was diluted with formic acid (15 ml) and stirred at 50° C. for17 h. The solution was diluted with toluene and then concentrated. Theresidue was purified by preparative HPLC using a gradient of 20–60% MeCNin 0.1M ammonium acetate buffer as eluent. The title compound wasobtained in 0.070 g (79%) as a white solid. NMR (400 MHz, DMSO-d₆):0.605–0.80 (6H, m), 0.80–1.60 (12H, m), 1.85 (3H, s), 2.10 (3H, s),2.60–2.80 (2H, m), 3.85 (2H, brs), 4.15–4.3 (1H, m), 4.65 (1H, d(AB)),4.70 (1H, d(AB)), 5.50 (1H, d), 6.60 (1H, s), 6.60–7.35 (11H, m), 8.30(1H, d), 8.40 (1H, d), 9.40 (1H, brs).

Example 311,1-Dioxo-3,3-dibutyl-5-phenyl-7-methyl-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 5; 0.050 g, 0.105 mmol),(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 86 of WO02/50051; 0.039 g, 0.148 mmol) and N-methylmorpholine (0.046 ml, 0.417mmol) in DCM (4 ml) was stirred at RT for 20 min, after which TBTU(0.044 g, 0.137 mmol) was added. After 1 h, the conversion to the ester(m/z: 721.2 (M+1)⁺) was completed. The solvent was removed under reducedpressure and the residue was dissolved in formic acid (5 ml). Thesolution was stirred for 17 hours and then concentrated. The residue waspurified by preparative HPLC using a gradient of 40–60% MeCN in 0.1Mammonium acetate buffer as eluent. The title compound was obtained in0.044 g (63%) as a white solid. NMR (400 MHz, DMSO-d₆): 0.65–0.80 (6H,m), 0.85–1.60 (12H, m), 2.10 (3H, s), 3.40–3.65 (2H, m), 3.70 (2H, bs),4.60 (1H, d(AB)), 4.70 (1H, d(AB)), 5.55 (1H, d), 6.70 (1H, s),6.80–7.50 (12H, m), 8.20–8.30 (1H, m), 8.55 (1H, d).

Example 321,1-Dioxo-3,3-dibutyl-5-phenyl-7-methyl-8-(N-{(R)-α-[N-((S)-1-carboxyropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 16; 0.050 g, 0.105 mmol),(R)-α-{N-[(S)-1-(t-butoxycarbonyl)propyl]carbamoyl}-4-hydroxybenzylamine(Method 19; 0.045 g, 0.146 mmol) and N-methylmorpholine (0.047 ml, 0.427mmol) in DCM (4 ml) was stirred at RT for 15 min, after which TBTU(0.044 g, 0.137 mmol) was added. After 17 h, the conversion to the ester(m/z: 765.7 (M+1)⁺) was completed. The solvent was removed under reducedpressure and the residue was dissolved in formic acid (5 ml). Thesolution was stirred for 3 days and then concentrated. The residue waspurified by preparative HPLC using a gradient of 40–60% MeCN in 0.1Mammonium acetate buffer as eluent. The title compound was obtained in0.017 g (23%) as a white solid. NMR (400 MHz, DMSO) 0.60 (3H, t),0.65–0.80 (6H, m), 0.85–1.75 (14H, m), 2.10 (3H, s), 3.75 (2H, bs),3.90–4.05 (1H, m), 4.60 (1H, d(AB)), 4.65 (1H, d(AB)), 5.50 (1H, d),6.65–7.30 (11H, m), 8.15 (1H, d), 8.40 (1H, d).

Example 331,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-{N-[(S)-2-(t-butoxy)-1-(t-butoxycarbonyl)ethyl]carbamoyl}propyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 20; 14 mg, 0.015 mmol) was dissolved in a mixture of DCM:TFA(3:1, 4 ml). The reaction mixture was stirred for 3.5 hours. The solventwas evaporated under reduced pressure. The product was purified bypreparative HPLC using a MeCN/0.1 M ammonium acetate buffer gradient(5/95 to 100/0) as eluent to give the title compound, 8 mg (65%). NMR(400 MHz): 0.7–0.83 (m, 9H), 0.9–1.40 (m, 8H), 1.40–1.52 (m, 2H),1.52–1.70 (m, 3H), 1.77–1.88 (m, 1H), 2.11 (s, 3H), 3.84–4.1 (m, 4H),4.29 (dd, 1H), 4.37 (t, 1H), 4.63 (ABq, 2H), 5.57 (s, 1H), 6.60 (s, 1H),7.04 (brt, 1H), 7.20 (brd, 2H), 7.25–7.40 (m, 6H), 7.47 (d, 2H); m/z812.3.

Example 341,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[2-(S)-2-(carboxy)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[2-(S)-2-(methoxycarbonyl)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 21; 23 mg, 0.030 mmol) was dissolved in TBF:H₂O (1:1, 1 ml).Lithium hydroxide (monohydrate, 2 mg, 0.048 mmol) was added and themixture was stirred for 2 hours. 50% Starting material remained soadditional lithium hydroxide (3 mg) was added and left for an hour. Thereaction was still not complete so further lithium hydroxide (2 mg) wasadded and the reaction was stirred overnight. The product was purifiedby preparative HPLC using a MeCN/0.1 M ammonium acetate buffer gradient(5/95 to 100/0) as eluent to give the title compound, 12 mg (53%). M/z753.04.

Example 351,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[2-(S)-2-(carboxy)azetidin-1-ylcarbonyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[2-(S)-2-(t-butoxycarbonyl)azetidin-1-ylcarbonyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 22; 27.5 mg, 0.035 mmol) was dissolved in DCM (3 ml) and TFA (1ml) was added. The reaction was stirred for 1.5 hours. The solvent wasevaporated under reduced pressure. The product was lyophilised to give25 mg of the title compound. M/z 722.92.

Example 361,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-1-carboxyethyl)carbamoyl]ethyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-{N-[(S)-1-(t-butoxycarbonyl)ethyl]carbamoyl}ethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepineMethod 26; 34 mg, 0.041 mmol) was dissolved in a mixture of DCM:TFA(3:1, 4 ml). The reaction mixture was stirred for 2 hours. The solventwas evaporated under reduced pressure. The product was purified bypreparative HPLC using a MeCN/0.1 M ammonium acetate buffer gradient(5/95 to 100/0) as eluent to give the title compound, 23 mg (72%). NMR(500 MHz, CD₃OD) 0.81 (bt, 6H), 0.88–1.54 (m, 16H),1.56–1.71 (m, 2H),2.11 (s, 3H), 3.8–4.2 (m, 2H), 4.33–4.42 (m, 2H), 4.66 (ABq, 2H), 5.55(s, 1H), 6.61 (s, 1H), 7.07 (t, 1H), 7.22 (brd, 2H), 7.28–7.43 (m, 6H),7.48 (d, 2H); m/z 782.1.

Example 371,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;and1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 51 mg, 0.080 mmol) was dissolved in 2 ml DMF. t-Butyl4-methyl D,L-leucinate (Method 27; 23 mg, 0.114 mmol),N-methylmorpholine (18 μl, 0.163 mmol) and TBTU (31 mg, 0.097 mmol) wereadded successively and the mixture was stirred for 2 hours. One drop offormic acid was added and the mixture was extracted between EtOAc andwater. The aqueous phase (pH=3) was washed with EtOAc. The combinedorganic layers were washed with 5% NaHCO₃ and brine and was then driedwith Na₂SO₄ and evaporated to dryness. The intermediate t-butyl ester ofthe title compound was confirmed. M/z: 823. DCM (2 ml) and TFA (0.5 ml)were added and the solution was stirred overnight. The mixture wasconcentrated and purified using preparative HPLC on a C8 column (50×250mm). A step gradient of MeCN (20–50%) in 0.1M ammonium acetate bufferwas used as eluent. The two diastereomers separated under theseconditions and they were collected and lyophilized separately. The firsteluting diastereomer was obtained in 5 mg (16% yield) and the secondeluting diastereomer was obtained in 3 mg (10% yield). The absoluteconfiguration was assigned by comparison of NMR-spectra with relatedcompounds and the first eluting diastereomer was found to be the(R,R)-diastereomer and the second eluting diastereomer was the(R,S)-diastereomer. M/z: 767. NMR of the (RR)-diastereomer (400 MHZ):0.79 (t, 6H), 0.95 (s, 9H), 0.99–1.22 (m, 6H), 1.25–1.39 (m, 2H),1.40–1.51 (m, 2H), 1.57–1.68 (m, 3H), 1.80 (dd, 1H), 2.08 (s, 3H), 3.95(brs, 2H), 4.47 (dd, 1H), 4.63 (Abq, 2H), 5.61 (s, 1H), 6.58 (s, 1H),7.04 (t, 1H), 7.20 (d, 2H), 7.25–7.35 (m, 6H), 7.43–7.47 (m, 2H). AndNMR of the (R,S)-diastereomer (400 MHz): 0.7 (s, 9H), 0.79 (t, 6H),0.99–1.22 (m, 6H), 1.25–1.39 (m, 2H) 1.40–1.51 (m, 3H), 1.55–1.70 (m,2H), 1.76 (dd, 1H), 2.12 (s, 3H), 3.95 (brs, 2H), 4.35 (dd, 1H), 4.60(Abq, 2H), 5.54 (s, 1H), 6.60 (s, 1H), 7.04 (t, 1H), 7.20 (d, 2H),7.24–7.37 (m, 6H), 7.39–7.46 (m, 2H).

Example 381,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R-1-carboxy-3,3-dimethylbutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

The title compound was prepared by the procedure of Example 37 startingfrom1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 18; 53 mg, 0.081 mmol). The intermediate t-butyl ester wasconfirmed. M/z: 839. Only one of the diastereomers were collected fromthe preparative HPLC purification of the racemic title compound. It wasobtained in 4 mg (12%) and was assigned to be the (R,R)-diastereomerfrom comparison of NMR-data of related compounds. M/z: 783. NMR (400MHz): 0.79 (t, 6H), 0.95 (s, 9H), 0.99–1.22 (m, 6H), 1.25–1.39 (m, 2H),1.40–1.51 (m, 2H), 1.56–1.68 (m, 3H), 1.79 (dd, 1H), 2.08 (s, 3H), 3.96(brs, 2H), 4.47 (dd, 1H), 4.62 (Abq, 2H), 5.47 (s, 1H), 6.58 (s, 1H),6.73 (d, 2H), 7.04 (t, 1H), 7.19 (d, 2H), 7.24–7.35 (m, 5H).

Example 391,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N-[(R)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4-hydroxybenzyl)carbamoylethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepineand1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(R)-α-{N-[(S)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 18; 55 mg, 0.084 mmol) and methyl 3-(trimethylsilyl)alaninate(Method 28; 19 mg, 0.108 mmol) were dissolved in 3.5 ml DMF. N-Methylmorpholine(18 μl, 0.163 mmol) and TBTU (32 mg, 0.101 mmol) were addedsuccessively and the mixture was stirred for 2 hours. One drop of formicacid was added and the mixture was then extracted between EtOAc andwater. The aqueous phase (pH=3) was washed with EtOAc. The combinedorganic phases were washed with 1% NaHCO₃, brine and was then dried withNa₂SO₄ and concentrated. The intermediate methyl ester was confirmed.M/z: 813. THF (2 ml), water (2 ml) and LiOH (10 mg, 0.418 mmol) wereadded and the mixture was stirred over night. The mixture was purifiedusing preparative HPLC on a C8 column (50×100 mm). A gradient from 20 to50% MeCN in 0.1M ammonium acetate buffer was used as eluent. The twodiastereomers were separated under these conditions and were collectedseparately. Lyophilisation yielded 8 mg (24% yield) of the first elutingdiastereomer and 8.4 mg (25% yield) of the second. The absoluteconfigurations were assigned from comparison with NMR-data of relatedcompounds and the first eluting diastereomer was found to be the(R,R)-diastereomer and the second eluting diastereomer was the(R,S)-diastereomer. M/z: 799. NMR of the (R,R)-diastereomer (400 Mz):−0.16 (s, 9H), 0.79 (t, 6H), 0.9–1.22 (m, 8H), 1.25–1.40 (m, 2H),1.40–1.52 (m, 2H), 1.55–1.68 (m, 2H), 2.11 (s, 3H), 3.95 (brs, 2H),4.29–4.35 (m, 1H), 4.58 (Abq, 2H), 5.45 (s, 1H), 6.59 (s, 1H), 6.73 (d,2H), 7.04 (t, 1H), 7.17–7.27 (m, 5H), 7.32 (t, 2H); and of the(R,S)-diastereomer (400 MHz): 0.04 (s, 9H), 0.79 (t, 6H), 1.00–1.22 (m,8H), 1.25–1.40 (m, 2H), 1.40–1.52 (m, 2H), 1.55–1.68 (m, 2H), 2.08(s,3H), 3.95 (brs, 2H), 4.40–4.46 (m, 1H), 4.62 (Abq, 2H), 5.49 (s 1H),6.58 (s, 1H), 6.73 (d, 2H), 7.04 (t, 1H), 7.14–7.36.(m, 7H).

Preparation of Starting Materials

The starting materials for the Examples above are either commerciallyavailable or are readily prepared by standard Methods from knownmaterials. For Example, the following reactions are an illustration, butnot a limitation, of some of the starting materials used in the abovereactions.

Method 1

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepineand1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5tetrahydro-1,2,5-benzothiadiazepine

To a suspension of1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(prepared according to WO 98/38182; 0.218 g, 5.65*10⁻⁴ mol) in DMF (5ml) was added NaSMe (0.210 g, 2.83 mmol, 95%), and the mixture wasstirred for 5 hours at 120° C. The solvent was removed under reducedpressure and the residue was partitioned between EtOAc and 0.5 M HCl.The aqueous layer was extracted twice more with EtOAc and the combinedorganic extracts were dried (MgSO₄) and concentrated. The residue wasdissolved in MeCN (7 ml) and ethyl bromoacetate (0.063 ml, 5.65*10⁻⁴mol), tetrabutylammonium bromide (0.018 g, 5.65*10⁻⁵ mol) and sodiumcarbonate (0.250 g, 2.36 mmol) were added. The mixture was stirred overnight at 80° C. The solvent was removed under reduced pressure and theresidue was partitioned between EtOAc and 0.5 M HCl. The organic layerwas washed with brine, dried (MgSO₄) and concentrated. Flashchromatography on silica gel (Hex:EtOAc-6:1) gave the title compounds ascolourless oils:1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,0.187 g (58%). NMR (400 MHz, CDCl₃) 0.70–0.80 (m, 6H), 0.90–1.70 (m,15H), 3.90 (brs, 2H), 4.25 (q, 2H), 4.35 (brs, 1H), 4.65 (s, 2H),6.95–7.40 (m, 7H); and1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,0.024 g (8%). NMR (400 MHz, CDCl₃) 0.70–0.85 (m, 6H), 0.90–1.70 (m,15H), 2.10 (s, 3H), 3.90 (brs, 2H), 4.20 (brs, 1H), 4.25 (q, 2H), 4.65(s, 2H), 6.55 (s, 1H), 6.95–7.35 (m, 6H).

Method 2

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 1; 0.184 g, 3.24*10⁻⁴ mol) in EtOH (7 ml) was added NaOH (0.052g, 1.30 mmol) and the mixture was stirred overnight. The solvent wasremoved under reduced pressure and the residue was partitioned betweenEtOAc and 0.5 M HCl. The aqueous layer was extracted twice more withEtOAc and the combined organic extracts were washed with brine andconcentrated. The crude product was purified by preparative HPLC usingan MeCN/ammonium acetate buffer as eluent and freeze-dried to give thetitle compound in 0.173 g (99%) as a white solid. NMR (400 MHz, CD₃OD)0.70–0.85 (m, 6H), 0.95–1.70 (m, 12H), 3.90 (brs, 2H), 4.50 (s, 2H),6.90–7.40 (m, 7H).

Method 3

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonyl-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 1; 0.024 g, 4.49*10⁻⁵ mol) in EtOH (3 ml) was added NaOH (0.007g, 1.80*10⁻⁴ mol) and the mixture was stirred over night. The solventwas removed under reduced pressure and the residue was purified bypreparative HPLC using an MeCN/ammonium acetate buffer as eluent andfreeze-dried. The title compound was obtained in 0.021 g (92%) as awhite solid. NMR (400 MHz, CD₃OD) 0.70–0.85 (m, 6H), 1.00–1.70 (m, 12H),2.10 (s, 3H),3.90 (brs, 2H), 4.55 (s, 2H), 6.60 (s, 1H), 6.90–7.35 (m,6H).

Method 3

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Alternative Preparation)

1,1-Dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-phenyl-7-methylthio-8-(t-butoxycarbonylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 25; 6.902 g, 10.11 mmol) was dissolved in a mixture of TFA (50ml) and Et₃Si (8 ml) and the solution was stirred for 90 min at RT. Thesolvent was removed under reduced pressure and the residue was dissolvedin t-BuOMe (100 ml). The organic phase was washed with water (20 ml) andthen extracted three times with diluted NaOH (2×50 ml 0.5M). Thecombined aqueous extracts were acidified with diluted HCl (70 ml, 1M)(pH 1–2) and were then extracted twice with t-BuOMe (2×50 ml). The etherlayer was washed with brine, dried over MgSO₄ and concentrated. 4.694 g(92%) of the desire product as brown oil were obtained. NMR (400 MHz,CD₃OD): 0.70–0.85 (m, 6H), 1.00–1.25 (m, 6H), 1.25–1.50 (m, 4H),1.55–1.70 (m 2H), 2.10 (s, 3H), 3.90 (brs, 2H), 4.55 (s, 2H), 6.60 (s,1H), 6.95–7.35 (m, 6H).

Method 4

(R)-N-Benzyloxycarbonyl-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine

(2R)-{[(Benzyloxy)carbonyl]amino}(phenyl)acetic acid (10 g, 35.0 mmol)and t-butylglycine hydrochloride (6.3 g, 37.4 mmol) was dissolved in DCM(200 ml) with 2,6-lutidine (8.2 ml, 70.4 mmol). After stirring 5 min at0° C. TBTU (12.4 g, 38.6 mmol) was added and stirring was continued for1.5 hours at 0° C. and 3.75 hours at room temperature. The reactionmixture was washed with water (2×100 ml), dried (MgSO₄) and purifiedwith flash chromatography (DCM:EtOAc 7:1→5:1) to give the title compound(13 g, 94%). NMR (500 MHz, CDCl₃): 1.45 (s, 9H), 3.84 (d, 1H), 4.00 (dd,1H), 5.10 (m, 2H),5.28 (brs, 1H), 6.13 (brs, 1H), 6.23 (brs, 1H),7.30–7.44 (m, 10H).

Method 5

(R)-α-[N-(t-Butoxycarbonylmethyl)carbamoyl]benzylamine

(R)-N-Benzyloxycarbonyl-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine(Method 4; 12.8 g, 32.2 mmol) was dissolved in EtOH (99%, 200 ml) andtoluene (50 ml). Pd/C (10%, 0.65 g) was added and hydrogenation wasperformed at atmospheric pressure for 5.5 hours at room temperature. Thereaction mixture was filtered through diatomaceous earth and thesolvents were evaporated to give the title compound (8.4 g, 99%). NMR(600 MHz, CDCl₃): 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H), 7.31–7.42(m, 5H), 7.51 (brs, 1H).

Method 6

2-{[(2R)-2-Amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acid

N-Boc-(D)-4-hydroxyphenylglycine (1.00 g, 3.21 mmol) was dissolved inDMF (5 ml) and tetrabutylammonium taurine (2.36 g, 6.42 mmol) was addedtogether with additionally 5 ml DMF. The resulting suspension was cooledon ice and TBTU (1.24 g, 3.85 mmol) was added. The ice bath was removedafter 30 min and the mixture was stirred for 2 hours before it wasfiltered and concentrated. TFA in DCM (20%, 20 ml) was added and thereaction mixture was stirred over night. Ethanol (20 ml) was added andthe solvents evaporated. The crude product was refluxed in ethanol (100ml) for 1 hour. Filtration yielded the pure title compound as a whitesolid, 626 mg (71%). NMR (DMSO-d₆): 2.4–2.6 (m, 2H), 3.2–3.4 (m, 2H),4.79 (s, 1H), 6.78 (d, 2H), 7.23 (d, 2H), 8.22 (t, 1H), 8.4 (brs, 3H),9.7 (s, 1H).

Method 7

4-(1-t-Butoxycarbonyl-1-aminomethyl)phenol

Sulfuric acid (conc, 1 ml) was added to a solution ofD-(R)-4-hydroxyphenylglycine (1.0 g, 6.0 mmol) in 1,4-dioxane (8 ml)placed in a Teflon® flask. The flask was cooled to −78° C. andisobutylene (8 g, 142.6 mmol, condensed at −78° C.) was added. The flaskwas placed in an autoclave at room temperature and stirred for 15 h. Theautoclave was cooled on ice before opened. The excess isobutylene wasallowed to evaporate and the remaining solution was poured into aqueousNaOH (2M, 20 ml) and was extracted with diethyl ether to remove formedby-product. The aqueous phase was slightly acidified to attain pH=10using 2M HCl and was extracted with diethyl ether (3×75 ml). The organicphase was washed with brine, dried and concentrated. The obtainedproduct was recrystallized in diethyl ether/hexane. Mass: 0.55 g (41%).NMR (600 MHz, CDCl₃) 1.45 (s, 9H), 4.45 (s, 1H), 6.8 (d, 2H), 7.25 (d,2H); m/z: 224.

Method 8

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(R)-α-{N-[(S)-1-(t-butoxycarbonyl)-4-(benzyloxycarbonylamino)butyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 53 mg, 0.083 mmol), tert-butylN⁵-[(benzyloxy)carbonyl]-L-ornithinate (35 mg, 0.098 mmol), N-methylmorpholine (0.027 m) were dissolved in DCM (5 ml). The mixture wasstirred at room temperature for 10 min, where after TBTU (32 mg, 0.10mmol) was added and the reaction mixture was stirred for 1.5 hours. Thesolvent was removed under reduced pressure and the residue was purifiedby chromatography using DCM:EtOAc, 5:1 as eluent to give the titlecompound 57 mg (72%). M/z=944.7 and 942.7 (M−R)⁻.

Method 9

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(t-butoxycarbonyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 3; 627 mg, 1.24 mmol) was dissolved in DCM (25 ml), tert-butyl(2R)-amino(phenyl)acetate (308 mg, 1.48 mmol), 2,6-dimethylpyridine (288μl, 2.47 mmol) and TBTU (477 mg, 1.48 mmol) were added. The mixture wasstirred for 3.5 hours. The reaction mixture was evaporated under reducedpressure. The product was purified using an Isolute column (10 g,silica). The product was eluted with a stepwise gradient using DCM:EtOAc100:0 then 95:5. Approximately 694 mg pure compound was collected.Another fraction was purified a second time using an Isolute column (10g, silica). The product was eluted with a stepwise gradient usingDCM:EtOAc 100:0,95:5 then 90:10. The pure fraction was added to thefirst fraction yielding 787 mg (91%) of the title compound. NMR (400MHz, CDCl₃) 0.78 (t, 6H), 0.92–1.12 (m, 4H), 1.12–1.46 (m, 6H), 1.54 (s,9H), 1.58‘1.72 (m, 2H), 2.14 (s, 3H), 3.8–4.05 (m, 2H), 4.32 (brs, NH),4.56 (ABq, 2H), 5.56 (d, 1H), 6.56 (s, 1H), 7.04 (t, 1H), 7.10 (brd, 2H)7.24–7.42 (m, 8H), 7.84 (d, NH); m/z 694.7 (M-H)⁻.

Method 10

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-2-(t-butoxycarbonyl)pyrrolidin-1-ylcarbonyl]benzyl}carbamoylmethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol) and tert-butyl L-prolinate (15 mg, 0.088mmol) were dissolved in DCM (2ml) and N-methylmorpholine (17.2 μl, 0.156mmol) and TBTU (45 mg, 0.14 mmol) were added. The reaction mixture wasstred for 3 hours then additional tert-butyl L-prolinate (15 mg, 0.088mmol) was added. The reaction mixture was stirred over night. Thereaction mixture was put directly on an Isolute column (2 g, silica).The product was eluted with a stepwise gradient using DCM:EtOAc 100:0,95:5, 90:10 then 80:20 to give the title compound (41 mg, 66%). M/z793.2.

Method 11

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(t-butoxycarbonylmethyl)-N-methylcarbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol) and tert-butyl N-methylglycinate (15 mg,0.10 mmol) were dissolved in DCM (2 ml) and N-methylmorpholine (17.2 μl,0.156 mmol) and TBTU (45 mg, 0.14 mmol) were added. The reaction mixturewas stirred for 4 hours. The reaction mixture was put directly on anIsolute column (2 g, silica). The product was eluted with a stepwisegradient using DCM:EtOAc 100:0, 95:5, 90:10 then 80:20 to give the titlecompound (30 mg, 50%). M/z 767.4.

Method 12

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N-[1-(R)-2-(R)-1-(t-butoxycarbonyl)-1-hydroxy-prop-2-yl]carbamoyl}benzyl)carbamoylmethoxyl]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol) and tert-butyl(2R,3R)-3-amino-2-hydroxybutanoate (15 mg, 0.086 mmol) were dissolved inDCM (2 ml) and DMF (1 ml) and N-methylmorpholine (17.2 μl, 0.156 mmol)and TBTU (45 mg, 0.14 mmol) were added. The reaction mixture was stirredfor 4 hours. The reaction mixture was put directly on an Isolute column(2 g, silica). The product was eluted with a stepwise gradient usingDCM:EtOAc 100:0, 95:5, 90:10 then 80:20 to give the title compound (33mg, 53%). M/z 797.3.

Method 13

t-ButylN-((2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoyl-o-(t-butyl)-L-serinate

(2R)-{[(Benzyloxy)carbonyl]amino}(phenyl)acetic acid (2.0 g, 7.0 mmol)and t-butyl O-(t-butyl)-L-serinate (2.0 g, 7.9 mmol) and 2.6-lutidinewere dissolved in DCM (30 ml). After stirring 5 min at 0° C. TBTU (2.5g, 7.8 mmol) was added and stirning was continued 30 min at 0° C. and 4h. at room temperature. The reaction mixture was washed with water(2×100 ml), dried and purified with flash chromatography (DCM) to givethe title compound (3.3 g, 97%). NMR (300 MHz): 1.05 (s, 9H), 1.45 (s,9H), 3.4–3.8 (m, 2H) 4.5 (brs, 1H), 4.85(s, 2H), 5.1 (s, 2H), 5.4 (s,1H), 7.25–7.5 (m, 10 H).

Method 14

t-Butyl N-[(2R)-2-amino-2-phenylethanoyl]-o-(t-butyl)-L-serinate

t-ButylN-((2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoyl)-o-(t-butyl)-L-serinate(Method 13; 3.3 g, 6.8 mmol) was dissolved in EtOH (95%, 30 ml) and acatalytic amount of Pd/C (5%)(50% in water) was added and hydrogenationwas performed at atmospheric pressure for 3 h. at room temperature. Thereaction mixture was filtered through diatomaceous earth and the solventwas evaporated to give the title compound (2.35 g, 98%). NMR (500 MHz):1.1 (s, 9H), 1.45 (s, 9H), 3.45–3.8 (m, 2H), 4.5 (t, 1H), 4.55 (s 1H),4.85 (s, 2H), 7.3–7.5 (m, 5H).

Method 15

1,1-Dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-phenyl-7-methyl-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

To a cooled solution (−78° C.) of1,1-dioxo-2-(4-methoxybenzyl)-3,3dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 23; 2.10 g, 3.41 mmol) in THF (50 ml) was added dropwise asolution of n-BuLi (2.35 ml, 3.75 mmol, 1.6 M in hexane). After stirringat −78° C. for 20 minutes, MeI (2.42 g, 17.1 mmol) was added. Themixture was stirred at −78° C. for 10 minutes and at room temperaturefor 18 hours. Diethyl ether (50 ml) was added and the organic phase waswashed with 10% NH₄Cl (aq, 50 ml) and brine (50 ml). After drying,filtration and concentration the crude product was subjected to flashchromatography (Hexane:EtOAc—95:5) to give 0.4 gram (21%) of the titleproduct as colourless oil. NMR (300 MHz, CDCl₃): 0.60–0.70 (m, 6H),0.70–0.90 (m, 4H), 0.90–1.35 (m, 8H), 2.00 (s, 3H), 3.70 (s, 3H), 3.80(s, 3H), 4.00–4.20 (m, 2H), 4.35–4.60 (m, 2H), 6.65–6.85 (m, 3H),6.90–7.10 (m, 3H), 7.15–7.30 (m, 5H).

Method 16

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

To a solution (0° C.) of trifluoroacetic acid (30 ml) and triethylsilane(1.03 g, 8.85 mmol) was added a solution of1,1-dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-phenyl-7-methyl-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 15; 0.92 g, 1.77 mmol) in DCM (2 ml). The reaction mixture wasstirred at room temperature for 30 minutes. After concentration of thereaction mixture, the residue was dissolved in diethyl ether (50 ml) andwashed with water (25 ml) and sodium bicarbonate (10%, 25 ml). Afterdrying, filtration and concentration the crude product was subjected toflash chromatography on silica gel (Hexane:EtOAc—90:10) to give 0.58 gof a grey solid. To a solution (0° C.) of this solid in dichloromethane(30 ml) was added dropwise BBr₃ in DCM (1M in DCM, 10.2 ml, 10.2 mmol).The reaction mixture was stirred at room temperature for 45 minutes andthen it was washed with sodium bicarbonate (10%, 25 ml) and water (25ml). After drying, filtration and concentration the crude product (0.55g, grey solid) was dissolved in MeCN (30 ml). The solution was addedK₂CO₃ (0.22 g, 1.58 mmol) and tetra-n-butyl ammonium bromide (10 mg)followed by ethyl bromoacetate (0.25 g, 1.51 mmol). The reaction mixturewas stirred at 80° C for 1.5 h and then evaporated under reducedpressure. The residue was dissolved in EtOAc (50 ml) and washed withNH₄Cl (aq, 10%) and brine. After drying, filtration and concentrationthe crude product was subjected to flash chromatography (Hex:EtOAc9:1–8:2) to afford 0.58 g of an off-white solid. The solid was dissolvedin THF:H₂O (4:1, 25ml) and LiOH (0.097 g, 2.31 mmol) was added. Thereaction mixture was stirred at room temperature for 40 min. The mixturewas evaporated under reduced pressure, dissolved in water (50 ml) andacidified with 1M HCl. The aqueous layer was extracted 2× with diethylether. Evaporation of the solvent under reduced pressure gave 0.46 g(55%) of the title compound. NMR (300 MHz, acetone-d₆); 0.70–0.90 (m,6H), 0.95–1.80 (m, 12H), 2.15 (s, 3H), 3.85–4.15 (m, 2H), 4.85 (s, 2H),6.00 (s, 1H), 6.80 (s, 1H), 6.90–7.05 (m, 1H), 7.10–7.45 (m, 5H).

Method 17

(R)-N-Benzyloxycarbonyl-α-carboxy-4-hydroxybenzylamine

(R)-p-Hydroxyphenylglycine (5.00 g, 29.9 mmol) was mixed with water (50ml). Sodium bicarbonate (6.3 g, 75.0 mmol) was added to the slurry and awhite suspension was the result after 10 min stirring. Benzylchloroformate (5.1 ml, 33.9 mmol) was added from a dropping funnel over20 min and the mixture was stirred vigorously. After 2 h, water (300 ml)was added and the suspension was extracted with ether (200 ml). Thewhite solid did not dissolve and more water and ether were added. LC/MSindicated that the solid was product. The clear part of the aqueousphase was collected and acidified upon a white precipitate was formed.This was left over the weekend and was then filtered off. The remainingaqueous phase containing undissolved material was acidified as well andwas extracted with EtOAc (3×). Also here a precipitate remained betweenthe phases. This was collected with the organic layer. The EtOAc phasewas evaporated. Toluene was added 2× to remoye water. The two fractionsof white solid were added together and recrystallized in DCM (200 ml).The cooled mixture was filtered and 4.77 g (53%) of white solid wereobtained. NMR (400 MHz, DMSO-d₆): 5.00 (1H, d), 5.00 (2H, s), 6.70 (2H,d), 7.05–7.50 (7H, m), 7.90 (1H, d)

Method 18

(R)-N-Benzyloxycarbonyl-α-{N-[(S)-1-(t-butoxycarbonyl)propyl]carbamoyl}-4-hydroxybenzylamine

A solution of (R)-N-benzyloxycarbonyl-α-carboxy-4-hydroxybenzylamine(Method 17; 2.00 g, 6.64 mmol), (2S)-2-amino butanoic acid t-butyl ester(1.30 g, 6.64 mmol) and N-methylmorpholine (2.0 g, 19.8 mmol) in DCM (30ml) was stirred at RT for 5 min, after which TBTU (2.60 g, 8.10 mmol)was added. The reaction mixture was stirred at ambient temperatureovernight. The solvent was removed under reduced pressure and theresidue was purified by flash chromatography on silica gelDCM:Acetone—60:40). The product was crystallized from toluene (20 ml)giving 1.85 g of the desired product as a white solid. NMR (400 MHz):0.80 (3H, t), 1.45 (9H, s), 1.50–1.80 (2H, m), 4.10–4.20 (1H, m), 5.05(1H, d(AB)), 5.15 (1H, d(AB)), 6.75 (2H, d), 7.20–7.40 (7H, m).

Method 19

(R)-α-{N-[(S)-1-(t-Butoxycarbonyl)propyl]carbamoyl}-4-hydroxybenzylamine

A mixture of(R)-N-Benzyloxycarbonyl-α-{N-[(S)-1-(t-butoxycarbonyl)propyl]carbamoyl}-4-hydroxybenzylamineMethod 18; 1.80 g, 4.07 mmol) and Pd/C (0.2 g, 5%) in ethanol (30 ml,95%) was stirred under hydrogen gas at room temperature for 2 hours. Thereaction mixture was filtered through silica gel (2 g) and concentrated.The residue was dissolved in acetone (20 ml) and methanesulphonic acid(0.40 g, 4.16 mmol) was added. No crystallization was obtained and thesolvent was removed under reduced pressure. The crude product waspurified by preparative HPLC using a gradient of 20–50% MeCN in 0.1Mammonium acetate buffer as eluent. The title compound was obtained in0.350 g (28%) as a white solid. NMR (400 MHz, DMSO-d₆): 0.75 (3H, t),1.40 (9H, s), 1.50–1.75 (2H, m), 2.70 (1H, s), 4.00–4.10 (1H, m), 4.30(1H, s), 6.65 (2H, d), 7.15 (2H, d), 8.15 (1H, d).

Method 20

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-{N-[(S)-2-(t-butoxy)-1-(t-butoxycarbonyl)ethyl]carbamoyl}propyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 6, 15 mg, 0.021 mmol), tert-butyl O-(tert-butyl)-L-serinatehydrochloride (5.4 mg, 0.021 mmol) and N-methylmorpholine (4.6 μl, 0.042mmol) was dissolved in DMF (1 ml). TBTU (12.5 mg, 0.039 mmol) was addedand the mixture was stirred for one hour. tert-butylO-(tert-butyl)-L-serinate hydrochloride (0.8 mg, 0.0031 mmol) was addedand the mixture was stirred for a couple of minutes. The solvent wasevaporated under reduced pressure and co-evaporated a few times withtoluene. The product was purified using a pre-packed ISOLUTE column(Silica, 2 g) and eluted with a stepwise gradient using DCM:EtOAc 100:0(10 ml) 95:5 (10 ml) 90:10 (10 ml) 80:20 (10 ml), to give 14 mg of thetitle compound. M/z 924.7.

Method 21

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[2-(S)-2-(methoxycarbonyl)-4-(R)-4-(hydroxy)-pyrrolidin-1-ylcarbonyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 54 mg, 0.084 mmol), methyl (4R)-4-hydroxy-L-prolinatehydrochloride (18.4 mg, 0.10 mmol) and N-methylmorpholine (13.9 μl, 0.13mmol) was dissolved in DMF (2 ml). TBTU (32.5 mg, 0.101 mmol) was addedand the mixture was stirred for three hours. The solvent was evaporatedunder reduced pressure. The product was purified two times using apre-packed ISOLUTE column (Silica, 2 g) and eluted with a stepwisegradient using DCM:EtOAc 100:0, 95:5, 90:10, 80:20 and 60:40, to give 23mg of the title compound. M/z 767.0.

Method 22

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[2-(S)-2-(t-butoxycarbonyl)azetidin-1-ylcarbonyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-12,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 50 mg, 0.078 mmol), tert-butyl (2S)-azetidine-2-carboxylate(17.4 mg, 0.111 mmol) and N-methylmorpholine (10.3 μl, 0.094 mmol) wasdissolved in DMF (2 ml). TBTU (30 mg, 0.094 mmol) was added and themixture was stirred for four hours. The solvent was evaporated underreduced pressure. The product was purified using a pre-packed ISOLUTEcolumn (Silica, 2 g) and eluted with a stepwise gradient using DCM:EtOAc100:0, 95:5, 90:10, 80:20, to give 27.5 mg of the title compound. M/z777.6 M-H)⁻.

Method 23

1,1-Dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(prepared according to WO 98/38182; 0.200 g, 0.404 mmol) in MeCN (5 ml)where added p-methoxybenzyl chloride (0.066 ml, 0.486 mmol), CsI (0.010g, 0.038 mmol) and Cs2CO3 (0.263 g, 0.807 mmol) and the mixture wasstirred at 60° C. for 4 h. The solvent was removed under reducedpressure and the residue was partitioned between EtOAc and 0.5M HCl(aq). The organic layer was washed with brine, dried over MgSO4 andconcentrated. The residue was filtered through silica gel(DCM:EtOAc-9:1) to give the title compound in 0.257 g (˜quant) as anoff-white solid. NMR (400 MHz, CDCl₃): 0.60–0.75 (m, 6H), 0.75–1.20 (m,8H), 1.25–1.45 (m, 2H), 1.80–2.00 (m, 2H), 3.80 (s, 3H), 3.90 (s, 3H),4.05–4.30 (m, 2H), 4.45–4.65 (m, 2H), 6.70–7.45 (m, 11H).

Method 24

1,1-Dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

NaSMe (0.150 g, 2.03 mmol, 95%) was added to a solution of1,1-dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 23; 0.249 g, 0.404 mmol) in DMF (5 ml). The mixture was stirredat RT for 2 h, after which the temperature was raised to 80° C. and moreNaSMe (0.090 g, 1.22 mmol) was added. After 20 h at 80° C. the mixturewas added water (5 ml) and 1M HCl (aq) (ph˜4). The solution wasextracted three times with Et₂O and the combined organic layers waswashed with brine, dried over MgSO₄ and concentrated. The crude productwas purified by flash chromatography on silica gel (Hex:EtOAc—4:1),which gave the title compound in 0.188 g (82%) as tan solid. NMR (500MHz, CDCl₃): 0.60–0.75 (m, 6H), 0.75–1.20 (m, 8H), 1.25–1.40 (m, 2H),1.80–2.00 (m, 2H), 2.20 (s, 3H), 3.80 (s, 3H), 4.20 (brs, 2H), 4.50(brs, 2H), 6.05 (brs, 1H), 6.75–6.85 (m, 3H), 7.00–7.10 (m, 3H),7.20–7.35 (m, 4H), 7.50 (s, 1H).

Method 25

1,1-Dioxo-2-(4-methoxybenzyl-3,3-dibutyl-5-phenyl-7-methylthio-8-(t-butoxycarbonylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of1,1-dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Method 24; 4.487 g, 7.889 mmol) in MeCN (100 ml) was added t-butylbromide (0.262 g, 0.813 mmol), t-butyl bromoacetate (1.46 ml, 9.880mmol) and potassium carbonate (anhydrous, 3.28 g, 23.7 mmol) in thisorder. The mixture was heated to 55° C. for 2.5 h, after which it wascooled to RT and left stirring over night. The solvent was evaporateduntil a yellowish slurry remained, which was extracted between diethylether (150 ml) and water (100 ml). The aqueous phase was washed withether (100 ml) and the combined ether layers were washed with 0.1M KHSO₄(aq, 100 ml), brine (100 ml) and were dried The ether was removed underreduced pressure and the beige solid obtained was dried under reducedpressure for 4 h (5.355 g, 99%). NMR (400 MHz, CDCl₃): 0.60–1.25 (m,14H), 1.25–1.40 (m, 2H), 1.50 (s, 9H), 1.75–2.00 (m, 2H), 2.10 (s, 3H),3.80 (s, 3H), 4.20 (brs, 2H), 4.50 (brs, 2H), 4.60 (s, 2H), 6.45 (s,1H), 6.75–6.85 (m, 2H), 7.00–7.15 (m, 3H), 7.20–7.40 (m, 5H).

Method 26

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-{N-[(S)-1-(t-butoxycarbonyl)ethyl]carbamoyl}ethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine(Example 25; 58 mg, 0.091 mmol), tert-butyl L-alanyl-L-alaninatehydrochloride (27.5 mg, 0.11 mmol) and N-methylmorpholine (20 μl, 0.18mmol) was dissolved in DMP (2 ml). TBTU (35 mg, 0.18 mmol) was added andthe mixture was stirred for 2–3 hours. The solvent was evaporated underreduced pressure. The product was purified using a pre-packed ISOLUTEcolumn (Silica, 2 g) and eluted with a stepwise gradient using DCM:EtOAc100:0, 95:5, 90:10 and 80:20 to give 34 mg (45%) of the title compound.M/z 838.5.

Method 27

tert-Butyl 4-methylleucinate

4-Methylleucine (500 mg, 3.44 mmol) was suspended in 10 ml t-butylacetate. Perchloric acid (0.2 ml, 3.49 mmol) was added and the flask wasstopped with a septum and stirred over night. Analysis was performedusing TLC DCM:MeOH, 9:1; staining with a ninhydrine/EtOH solution). Thesolution was poured into a flask containing 30 ml EtOAc and 30 ml 5%Na₂CO₃. The aq-layer turned acidic and 2M NaOH was added until pH wasapproximately 7. The phases were separated and the aq-phase was washedwith 2×30 ml EtOAc. The combined organic phases were washed with brine,dried with Na₂SO₄ and evaporated. A oil was obtained which wasco-evaporated with toluene and then with diethyl ether before beingplaced under vacuum for two days. Mass 665 mg (96% yield). NMR (CDCl₃):1.0 (s, 9H), 1.5 (s, 9H), 1.65–1.95 (m, 2H), 3.82 (t, 1H).

Method 28

Methyl 3-(trimethylsilyl)alaninate

3-Trimethylsilyl alanine (J. Organomet. Chem., 628, (2001), 183–194; 19mg, 0.118 mmol) was mixed with 3 ml BF₃-MeOH (14%, 3.7 mmol) in a sealedtube and heated to 70° C. Analysis was performed using TLC (MeOH:DCM1:9, stained w. ninhydrine in ethanol). The mixture was heated for 3 hand was then cooled to ambient temperature. The mixture was poured intoa mixture of 3 ml EtOAc and 2 ml water containing Na₂CO₃. More Na₂CO₃(5%-aq) was added until pH ca 7. The aqueous phase was washed with EtOAc(2×3 ml). The combined organic layers were washed with brine (1 ml),dried with Na₂SO₄ and evaporated. The product was obtained as a whitefilm. Mass: 19 mg (92% yield). NMR (CDCl₃): 0.1 (s, 9H), 1.2–1.4 (m,2H), 3.8 (s, 3H), 4.2 (brs, 1H).

1. A compound of formula (I):

wherein: R^(v) is selected from hydrogen or C₁₋₆alkyl; One of R¹ and R²are selected from hydrogen, C₁₋₆alkyl or C₂₋₆alkenyl and the other isselected from C₁₋₆alkyl or C₂₋₆alkenyl; R^(x) and R^(y) areindependently selected from hydrogen, hydroxy, amino, mercapto,C₁₋₆alkyl, C₁₋₆alkoxy, N-(C₁₋₆alkyl)amino, N,N-(C₁₋₆alkyl)₂amino,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2; M is selected from —N— or —CH—;R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N-(C₁₋₆alkyl)amino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N-(C₁₋₆alkyl)carbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N-(C₁₋₆alkyl)sulphamoyl andN,N-(C₁₋₆alkyl)₂sulphamoyl; v is 0–5; one of R⁴ and R⁵ is a group offormula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino,N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl,N,N-(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a), wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N-(C₁₋₄alkyl)sulphamoyl andN,N-(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶; X is —O—,—N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) is hydrogen orC₁₋₆alkyl and b is 0–2; Ring A is aryl or heteroaryl; wherein Ring A isoptionally substituted by one or more substituents selected from R¹⁷; R⁷is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸; R⁸is hydrogen or C₁₋₄alkyl; R⁹ is hydrogen or C₁₋₄alkyl; R¹⁰ is hydrogen,C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ is optionallysubstituted by one or more substituents selected from R¹⁹; R¹¹ iscarboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆allkyl; or R¹¹ is agroup of formula (IB) or (IC):

R¹⁹, R²⁰, R²⁴ and R²⁶ are independently selected from halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino,C₁₋₄alkanoylamino, N-(C₁₋₄alkyl)carbamoyl, N,N-(C₁₋₄alkyl)₂carbamoyl,C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl,N-(C₁₋₄alkyl)sulphamoyl, N,N-(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl,heterocyclyl, benzyloxycarbonylamino, (C₁₋₄alkyl)₃silyl, sulpho,sulphino, amidino, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)),—P(O)(OH)(R^(a)) or —P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) areindependently selected from C₁₋₆alkyl; wherein R¹⁹, R²⁰, R²⁴ and R²⁶ maybe independently optionally substituted on carbon by one or more R²²;R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, tifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl; R²³ is carboxy,sulpho, sulphino, phosphono, —P(O)(OR^(g))(OR^(h)), —P(O)(OH)(OR^(g)),—P(O)(OH)(R^(g)) or —P(O)(OR^(g))(R^(h)) wherein R^(g) and R^(h) areindependently selected from C₁₋₆alkyl; R²⁵ is selected from C₁₋₆alkyl,C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,N-(C₁₋₆alkyl)carbamoyl, N,N-(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein “heteroaryl” isa totally unsaturated, mono or bicyclic ring containing 3–12 atoms ofwhich at least one atom is chosen from nitrogen, sulphur or oxygen,which may, unless otherwise specified, be carbon or nitrogen linked;wherein a “heterocyclyl” is a saturated, partially saturated orunsaturated, mono or bicyclic ring containing 3–12 atoms of which atleast one atom is chosen from nitrogen, sulphur or oxygen, which may,unless otherwise specified, be carbon or nitrogen linked, wherein a CH₂group can optionally be replaced by a C(O) or a ring sulphur atom may beoptionally oxidised to form the S oxides; and wherein a “carbocyclyl” isa saturated, partially saturated or unsaturated, mono or bicyclic carbonring that contains 3–12 atoms; wherein a CH₂ group can optionally bereplaced by a C(O); or a pharmaceutically acceptable salt thereof.
 2. Acompound of formula (I) as claimed in claim 1 wherein R^(v) is hydrogenor a pharmaceutically acceptable salt thereof.
 3. A compound of formula(I) as claimed in claim 1 wherein R¹ and R² are both butyl or apharmaceutically acceptable salt thereof.
 4. A compound of formula (I)as claimed in claim 1 wherein R^(x) and R^(y) are both hydrogen or apharmaceutically acceptable salt thereof.
 5. A compound of formula (I)as claimed in claim 1 wherein M is —N— or a pharmaceutically acceptablesalt thereof.
 6. A compound of formula (I) as claimed in claim 1 whereinv is 0 or a pharmaceutically acceptable salt thereof.
 7. A compound offormula (I) as claimed in claim 1 wherein R³ and R⁶ are hydrogen or apharmaceutically acceptable salt thereof.
 8. A compound of formula (I)as claimed in claim 1 wherein R⁴ is bromo, methyl or methylthio or apharmaceutically acceptable salt thereof.
 9. A compound of formula (I)as claimed in claim 1 wherein R⁵ is a group of formula (IA) (as depictedin claim 1) wherein: X is —O—; Ring A is phenyl optionally substitutedby one or more substituents selected from R¹⁷; n is 1; R⁷ is hydrogen;R⁸ is hydrogen; R⁹ is hydrogen; m is 0; R¹¹ is carboxy, a group offormula (IB) (as depicted above) or a group of formula (IC) (as depictedabove) wherein: R¹² is hydrogen or C₁₋₄alkyl; p is 1 or 2; R¹³ ishydrogen or C₁₋₆alkyl optionally substituted by R²⁰ wherein R²⁰ ishydroxy, carbamoyl, amino, benzyloxycarbonylamino, C₁₋₄alkylS(O)_(a)wherein a is 0 or (C₁₋₄alkyl)₃silyl; R¹⁴ is hydrogen or hydroxy orC₁₋₆alkyl; wherein R¹⁴ may be optionally substituted by one or moresubstituents selected from R²⁰; Y is —N(R^(n))C(O)— wherein R^(n) ishydrogen; q is 0 or 1; r is 0 or 1; R¹⁵ is carboxy or sulpho; R¹⁷ ishydroxy; and R²⁰ is selected from hydroxy; Ring B is pyrrolidin-1-yl orazetidinyl substituted on carbon by one group selected from R²³, andoptionally additionally substituted on carbon by one or more R²⁴;wherein R²³ is carboxy and R²⁴ is hydroxy; or a pharmaceuticallyacceptable salt thereof.
 10. A compound of formula (I) as claimed inclaim 1 wherein: R^(v) is hydrogen; R¹ and R² are both butyl; R^(x) andR^(y) are both hydrogen; M is —N—; v is 0; R³ and R⁶ are hydrogen; R⁴ isbromo, methyl or methylthio; and R⁵ isN-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxyethyl) carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-carbamoyl-ethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-hydroxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-3-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(1-(S)-1-carboxy-2-(S)-2-methylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-4-aminobutyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-{N-[(S)-1-carboxy-4-(benzyloxycarbonylamino)butyl]carbamoyl}benzyl)carbamoylmethoxy,N-[(R)-α-((S)-2-carboxypyrrolidin-1-ylcarbonyl)benzyl]carbamoylmethoxy,N-{(R)-α-[N-(carboxymethyl)-N-methylcarbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(1-(R)-2-(R)-1-carboxy-1-hydroxyprop-2-yl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-(sulphomethyl)carbamoyl]benzyl}carbamoylmethoxy,N-((R)-α-carboxybenzyl)carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[2-(S)-2-(carboxy)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl}carbamoylmethoxy,N-{(R)-α-[2-(S)-2-(carboxy)azetidin-1-ylcarbonyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-{(S)-1-[N-((S)-1-carboxyethyl)carbamoyl]ethyl}carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((S)-1-carboxy-3,3-dimethylbutyl)carbamoyl]benzyl}carbamoylmethoxy,N-{(R)-α-[N-((R)-1-carboxy-3,3-dimethylbutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy,N-((R)-α-{N-[(S)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxyorN-((R)-α-{N-[(R)-1-carboxy-2-(trimethylsilyl)ethyl]carbamoyl}-4-hydroxybenzyl)carbamoylmethoxy;or a pharmaceutically acceptable salt thereof.
 11. A compound of formula(I) as claimed in claim 1 selected from:1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;and1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or a pharmaceutically acceptable salt thereof.
 12. A process forpreparing a compound of formula (I) as claimed in claim 1 or apharmaceutically acceptable salt thereof which process comprises of:Process 1): for compounds of formula (I) wherein X is —O—, —NR^(a) or—S—; reacting a compound of formula (IIa) or (IIb):

 with a compound of formula (III):

 wherein L is a displaceable group; Process 2): reacting an acid offormula (IVa) or (IVb):

 or an activated derivative thereof; with an amine of formula (V):

Process 3): for compounds of formula (I) wherein R¹¹ is a group offormula (IB); reacting a compound of formula (I) wherein R¹¹ is carboxywith an amine of formula (VI):

Process 4) for compounds of formula (I) wherein one of R⁴ and R⁵ areindependently selected from C₁₋₆alkylthio optionally substituted oncarbon by one or more R¹⁷; reacting a compound of formula (VIIa) or(VIlb):

 wherein L is a displaceable group; with a thiol of formula (VIII):R^(m)—H  (VIII)  wherein R^(m) is C₁₋₆alkylthio optionally substitutedon carbon by one or more R¹⁶; Process 5): for compounds of formula (I)wherein R¹¹ is carboxy, deprotecting a compound of formula (IXa):

 wherein R^(p) together with the —OC(O)— group to which it is attachedforms an ester; Process 6): for compounds of formula (I) wherein R¹¹ isa group of formula (IB) and R¹⁵ is carboxy, deprotecting a compound offormula (Xa):

 wherein R^(p) together with the —OC(O)— group to which it is attachedforms an ester; or Process 7): for compounds of formula (I) wherein R¹¹is a group of formula (IB) and N(R^(n))C(O)—; reacting an acid offormula (XIa):

 or an activated derivative thereof; with an amine of formula (XII):

and thereafter if necessary or desirable: i) converting a compound ofthe formula (I) into another compound of the formula (I); ii) removingany protecting groups; iii) forming a pharmaceutically acceptable salt.13. A pharmaceutical composition which comprises a compound of formula(I), or a pharmaceutically acceptable salt thereof, as claimed in anyone of claims 1 to 11, in association with a pharmaceutically-acceptablediluent or carrier.
 14. A compound selected from the group consistingof:1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;and1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or a pharmaceutically acceptable salt thereof.
 15. A compound selectedfrom the group consisting of: a compound of formula (IXa):

 a compound of formula (IXb):

 a compound of formula (Xa):

 and a compound of formula (Xb):

wherein, in each said compound, R^(v), R¹, R², M, R^(x), R^(y), R^(z),R³, R⁴, R⁵, R⁶, X, Ring A, R⁷, R⁸, R⁹, R¹⁰, R¹¹, Y, R¹², R¹³, R¹⁴, R¹⁵,p, q, r, m, n, Ring B, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵and R²⁶ are as defined in claim 1, and R^(p) is C₁₋₆alkyl orphenylC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.